While Ichigo Momomiya is on her first date with Masaya Aoyama, she is bathed in a strange light and sees herself being merged with a cat. Afterwards, she begins to display cat-like behaviors. The next day, Ichigo follows Masaya into a park, where a strange jellyfish-like creature takes over a rat's body, turning it into a monster. Ryou Shirogane saves Ichigo and gives her a pendant allowing her to transform into Mew Ichigo. With her new powers, she defeats the monster, turning it back into a normal rat. Afterwards, Ryou refuses to explain what just occurred, so the newly arrived Keiichiro Akasaka offers to do so instead.

Ryou and Keiichiro tell Ichigo that the creature she saw was a parasitic alien, called a chimera anima. To stop them, the Mew Project infused five girls with the DNA from specific endangered species, enabling the girls to become "mew mews". Ichigo begins working at Cafe Mew Mew while searching for the other four girls who bear the Mew marks. Keiichiro gives her a robot, Masha, to help with her work. While going home, Ichigo meets Mint Aizawa and her dog. Later, Ichigo visits Mint's home to return a handkerchief, but Mint's dog becomes infected by a chimera anima. During the battle, Ichigo discovers that Mint is the second mew mew, Mew Mint. They defeat the monster, returning the dog to normal. Mint joins Ichigo in working at the café.

Ichigo meets a shy and timid girl named Lettuce Midorikawa. Later at the café, Ichigo sees her with three other girls, who are trying to coerce an unwilling Lettuce to try to photograph a rumored school ghost. Ichigo "accidentally" dumps parfaits on them to get them to leave Lettuce alone. After work, Mint and Ichigo go to the school to investigate the "ghost". Instead, they find Lettuce who was afraid of being isolated because of her new powers and started "haunting" the pool. After a brief fight, Ichigo and Mint calm her by explaining her Mew powers and welcome her to the team. While Ichigo is walking home, an alien named Kish appears, steals her first kiss, and introduces himself before disappearing again.

Upset about her first kiss stolen, Ichigo avoids Aoyama, even declining a date with him. While looking for chimera animas, Masha leads her to the park where she runs into Masaya. Resolved to forget the kiss, Ichigo agrees to spend time with him. Kish attacks the park, turning a lion into a chimera anima. Ichigo leaves a worried Masaya behind as she hides to transform and fight. After Mew Mint and Mew Lettuce arrive, the three defeat the monster. When Ichigo finds Masaya, he scolds her for running away. As they walk home, he explains his worry about her, and Ichigo promises not to do it again.

The school rhythmic gymnastics team sees Ichigo avoid the path of an on-coming bus by leaping over it, and the team recruits her. A promise from Masaya to come and cheer for her at the competition changes Ichigo's participation from reluctant to enthusiastic. After Ichigo's spectacular individual performance, Kish attacks with a chimera anima. After the Mew Mews defeat the monster, competition continues; but Ichigo's performance drops during her team's round due to exhaustion from the fight. The team is happy with their second place win and names Ichigo the team's Most Valuable Player.

While cleaning the café, a woman approaches Ichigo and Lettuce and begins speaking to them in English (Spanish in the 4Kids dub), but they cannot understand her. Masaya appears and translates for them. The woman, Mary McGuire (Maria Rivera in the 4Kids Dub), is a pianist who Ryou asked for a performance at an upcoming formal party to reward the girls for their good work. During the party, Kish appears and uses a new technique to steal Mary's (Maria's) spirit to create a chimera anima. During the battle, he mentions the name of the mysterious alien leader, Deep Blue. The girls use Mary's (Maria's) music to weaken the monster, enabling the girls to defeat it and return her spirit back to her body.

Returning from the grocery store, Ichigo stops to rest on a bench. A young girl, Pudding Fong, begins performing acrobatic tricks in front of her and then demands a tip. Ichigo gives her a piece of candy then runs off. Angered, Pudding causes Ichigo's cat ears and tail to pop out. Amazed, Pudding chases Ichigo wanting her own set of ears and tail in order to make money. Ichigo finally yells at her but later at the café feels sorry for the girl as they wonder why she wants to make money so badly and goes to apologize. The next day, Kish attempts to steal Pudding's spirit, but the Mew Mews stop him. Using the spirit of another human stolen earlier, he attacks with a chimera anima. While protecting Ichigo and Mint, the monster's attacks; Pudding's mew mark is revealed and she transforms into Mew Pudding. She quickly helps them defeat the monster and is ecstatic to join the Mew Mews.

The girls win a day-trip to a resort in the mountains. On the way up the mountain, they stop at a shrine to eat lunch where a boy named Masazou Aoyamada yells at them for desecrating the shrine of Bacchigappa, the god of the mountain. The girls find a natural hot spring and stop to relax. There they learn that the resort is under construction and that their prize trip is for the following year. Masazou tries to stop the construction workers, claiming that the work has scared away the local otters and is destroying their habitat. Kish arrives and steals the boy's spirit to create a chimera anima. The Mew Mews defeat the monster and restore Masazou's spirit. The incident prompts the other villagers to join in Masazou's cause to oppose the construction.

While at Mint's house to borrow a dress, Ichigo meets her older brother, Seiji, who is going to study abroad. She is saddened to learn that they have grown apart after seeing an old photo of the two. Wanting to help the siblings reconcile, Ichigo invites him to attend Mint's next ballet performance. When the girls bring Seiji to Mint's dressing room before the performance, Mint maintains her distance from her brother. As he is leaving, a chimera anima attacks and Seiji tries to protect Mint. After the Mew Mews defeat it, Mint again tells Seiji he should not waste his time there. He gives her a bouquet of flowers and tells her that she is still important to him.

One night, a mysterious girl saves two people from a chimera anima. At the café, the girls read a newspaper article about the incident and realize that none of them is the girl shown in the picture. Mint arrives and recognizes the girl as Zakuro Fujiwara, a famous model whom she idolizes. Ryou sends the girls to an audition to meet her, but Pudding's tricks nearly get them kicked out. That night, the girls find her praying at a church where she is attacked by a flock of crows infected by chimera animas. Before the girls acted, Zakuro transforms and defeats them all. Afterwards, the girls are shocked with she refuses to join them and dismisses them as annoying.

Mint is upset by Zakuro's rejection, and the others try to cheer her up. Ichigo and the others go to talk to Zakuro. Meanwhile, Kish approaches Zakuro and offers her a deal to return her body to normal if she joins him. When the girls arrive, Kish traps Mint, Lettuce, and Pudding in an alternate dimension. He then demands a fight between Ichigo and Zakuro in exchange for the trapped friends. Ichigo refuses and returns to the café where Ryou encourages her to trust in Zakuro and share her feelings. While shooting a television show, Zakuro is attacked by a chimera anima. Ichigo arrives and battles the monster while Zakuro saves the others. After its defeat, Zakuro agrees to be a part of the team. Apparently, the entire battle was aired on live television, and so they introduce themselves to Tokyo as the protectors of justice, "Tokyo Mew Mew".

Masaya takes Ichigo to Inohara Park to show her a large cherry tree that is unusually blooming out of season. The next day, Keiichiro discovers that five cherry trees have been infected by the aliens explaining the early blooming. The Mew Mews set out to destroy them simultaneously, or the trees will release a poison dangerous to Tokyo. Mew Ichigo takes the tree in Inohara Park, where Kish waits for her. A fight keeps Ichigo from attacking the tree, and it begins releasing its poison. Ichigo jumps into the tree and successfully destroys it. After Kish leaves, Mew Ichigo finds Masaya standing behind her after he called out "Ichigo".

Worried Masaya discovered her identity, Ichigo avoids him. Later, Ichigo intends to cheer for Masaya during a kendo match but is unable to face him. Later, a jealous Kish attacks him with a chimera anima capable of recreating itself when attacked. Ichigo tries to fight the monster but is unable to destroy it. Kish tells her that he will let Masaya go if Ichigo becomes his, but Ichigo refuses and instead dives into the slime and grabs Masaya's hand. Her body begins to glow and she breaks free, destroying the monster. Kish retreats and Masaya apologizes to Mew Ichigo for calling her "Ichigo", explaining that she looked like someone he knew. Later, he thanks Ichigo for coming to cheer for him and ties a bell collar around her neck so she cannot run from him anymore. Disappointed in Kish's continued failures, Deep Blue sends two more aliens, Pie and Tart, to help him destroy the Mew Mews.

Keiichiro begins making a beautiful birthday cake for someone, and the girls ponder whom it might be for. Later, Ichigo meets a woman named Rei studying butterflies. She later learns that Rei is Keiichiro's ex-girlfriend, and the intended recipient of the cake. Even though they separated due to their different interests and jobs, he continues making her new birthday cakes for her. The girls try to get them meet again to resolve their lingering feelings. At Rei's house, her spirit is stolen by Pie and Tart and used to make a chimera anima. With help from Keiichiro, they are able to defeat the monster and retrieve Rei's spirit. In the end, Rei and Keiichiro truly go their separate ways.

The girls wonder about Masha's usefulness beyond just detecting chimera animas and eating the parasites. The discussion leads Masha to question his confidence. While the Mew Mews fight a chimera anima, he tries to fight alongside and ends up swallowed by the monster. Tart and Pie retreat to the alien dimension. Upon discovery of Masha, Pie tries to extract Masha's data. In turn, Masha uses the connection to the aliens' computers to send a message to the girls, enabling them to find a way to the dimension. Before they leave, Ryou gives Ichigo a new weapon, the Mewberry Rod. When the girls reach the alien area, they are quickly captured, but Masha gets himself free and rescues them. Ichigo uses her new attack to destroy the chimera anima, allowing them to return to their own dimension. Masha promises not to try to fight anymore.

Lettuce meets a young man named Norihiro at the library. She falls in love with him and begins going there every day to see him. When he gives her a present, the girls encourage her to tell him how she feels. During their next meeting at the library, they are attacked by a chimera anima. Seeing Norihiro rush to protect the young librarian, Satsuki, Lettuce realizes that she is the girl he really loves. The other Mew Mews arrive, but the monster begins reading a dull book in a hypnotic voice, putting all of the girls to sleep except the book loving Lettuce. She transforms and defeats the monster. Later, she sees Norihiro gives Satsuki an engagement ring. Though sad at how her first love ended, she says she is happy she was able to love someone.

The data gathered by Masha reveals that the aliens originally inhabited the earth, but had to leave because of changes in the environment, ending up on an even worse planet. Ichigo is upset at this, but Ryou reminds her that it is not an excuse for trying to kill humans. Ichigo goes on a date with Masaya, which cheers her up, but the next day she is sick with a cold. The girls and Masaya visit, but after he leaves Kish appears. Ichigo escapes out a window, while the others prepare to battle multiple chimera animas released by Pie and Tart. Too weak to fight, Ichigo is unable to protect herself from Kish, but is suddenly rescued by a mysterious alien who introduces himself as The Blue Knight.

While the four Mew Mews are fighting the chimera animas created by Pie and Tart, the Blue Knight battles Kish. He is injured while protecting Ichigo, but the arrival of the other Mew Mews causes the aliens to retreat. Before leaving, the Blue Knight tells Ichigo that he was born to protect her. Ryou appears out of nowhere to catch Mew Ichigo as she faints from her illness. At the café, the girls wonder who the Blue Knight is, and decide it must be Ryou but he claims he does not know anything about it. While on a date with Masaya, Ichigo is distracted and imagining she is seeing Ryou, but eventually discovers it is actually Lettuce and Pudding who were spying on the couple out of concern for Ichigo. After Masaya leaves, Ichigo admits she also believes Ryou is the Blue Knight. That evening while Ichigo is cleaning the café, Ryou surprises her by inviting her to go to the beach.

At the beach, the girls enjoy swimming and playing in the water. However, Lettuce does not know how to swim. A girl named Iruka is being picked on for her inability to swim despite having a name meaning "dolphin". Lettuce offers support. Later, Iruka admits her ability to swim but she has a fear for water. To encourage her, Lettuce jumps into the water but nearly drowns shaking her confidence. The next day, the aliens attack the beach with chimera animas and cause a storm to appear. During the fight, one of the boys from the day before falls into the water. Iruka jumps in to save him, and Mew Lettuce follows to rescue them both. Struggling to swim, Lettuce's legs change into a porpoise tail, enabling her to swim easily and save the children.

When Pudding falls sick, Ichigo, Mint, and Lettuce agree to go to pick up Pudding's little sister Heicha from school. Heicha's teacher explains that Pudding's mother died and her father is always traveling, so Pudding is the primary caretaker of her five siblings. However, the little girl refuses to leave the school with the others, but Pudding arrives to get her. The others go with them back home to help care for the others. The next day, Heicha's teacher drives her home and offers to help Pudding, but Pudding declines her offer. Tart appears and steals the teacher's spirit to make a chimera anima. Pudding is still too sick to fight, but the others arrive and defeat it. Later, the teacher offers to drive Heicha to school, but Pudding says she would not get to spend time with her little sister like that. Instead, she asks the teacher if she can pretend to be her mom for a little while.

Mint has a strange dream in which she is talking with her merged animal, the ultramarine lorikeet. Later at the café, Ryou and Keiichiro tell the girls about a substance called mew aqua and its power. After her dream, Mint is concerned about their mission. When she learns the late-arriving Ichigo was on a date with Masaya, she gets angry and stomps out of the café. Later the girls receive a package with Mint's pendant and uniform in it. Zakuro goes to talk to her while the others begin searching for mew aqua. The aliens are also searching for it and find it just as Ichigo, Lettuce, and Pudding appear. Kish merges five parasites into the mew aqua, creating a powerful new chimera anima. The girls are struggling to fight it but Mew Zakuro is able to convince Mint to transform and together they defeat the monster. They learn the mew aqua was a fake and Mint apologizes to Ichigo for her earlier actions.

As summer break comes to an end, Ichigo has to scramble to finish all of her homework before the start of school. The aliens also are enjoying the last day of summer and are avoiding working, but finally send Tart to continue their plans. Though she has no time left, Ichigo agrees to go on a date with Masaya, but just as she arrives, she is called back to the café to help clean up the mess made by water pipes. Ichigo laments her undone homework but gets no help. Masha detects a chimera anima just before they are attacked by one created by Tart. Angry, Mew Ichigo quickly defeats it, but Tart releases more. Ichigo must spend the rest of the day with the others defeating the monsters, leaving no time to finish her homework.

Ichigo discovers that her school friends Moe and Miwa have developed crushes on Ryou and Keiichiro. Though Ichigo fears her friends will be disappointed, she agrees to help them. They make gifts for the boys, but when they go to the café to present them, the boys are busy searching for mew aqua and ignore them. Hurt, the girls run out of the café and Ichigo scolds Ryou and Keiichiro for ignoring the girls' feelings. Kish appears and creates two chimera animas from the spirits he stole from Miwa and Mow. Ichigo defeats them, and the girls spirits' are restored, but Kish takes a light out of the lake before he disappears. When Mow and Miwa wake up, Ryou and Keiichiro properly thank them for the gifts. The girls decide to start a fan club for them.

Zakuro takes Ichigo to the rehearsal of a jewelry company premiere where she befriends a clumsy crew member named Tsukiko. Tsukiko really wants Zakuro to wear a rainbow stone necklace for the show, but both the stage manager and Zakuro reject it for being too modest. Ryou, Keiichiro, and the aliens all believe the stone is made from mew aqua. During the show, Kish tries to steal the necklace. The Mew Mews fight for the stone but are having a hard time with the chimera anima Kish is using until they are helped by the Blue Knight. After the monster is defeated, they discover the stone is not mew aqua. Deciding it is not an ordinary stone, Zakuro arranges for Tsukiko herself to appear in the show wearing a simple white dress and the necklace, proving Tsukiko's claim that the stone can make any girl shine.

When Ryou and Keiichiro discover that mew aqua is most likely to be found underground, Ichigo cancels a date with Masaya to search for it. Ryou and Keiichiro decide to use an ancient rod unearthed at the archaeological site where they first learned about the aliens. Meanwhile, the aliens are already underground, searching with chimera animas. Kish also plants a cocoon at the top of Tokyo Tower. In one month, a moth will hatch from it and release pollutants over Tokyo. Tired from searching for the mew aqua, a grouchy Ichigo accidentally yells at Masaya. When she nearly faints, he takes her to the nurse's office. Talking with him restores her good mood and they agree to go on a date. Later, Ryou lets the girls leave work early, but then Masha and Keiichiro discover the cocoon, and the Mew Mews rush to Tokyo Tower.