Spider-Man's dream of joining the Avengers becomes a nightmare when Loki switches bodies with the web-slinger, turning his new teammates against him. Spider-Man and his friends team up with the Avengers to stop Loki and Doctor Octopus from destroying New York City with an army of Venomized monsters.

Spider-Man sees what the world would be like without him when Nightmare takes the web-slinger on a journey through his past, present, and future.

While chasing Green Goblin across the Multiverse, Spider-Man arrives in the Marvel Noir universe where he helps Spider-Man Noir renew his friendship with Marry Jane. Then Spider-Man heads to a cartoonish world inhabited by anthropomorphic animals where he helps Peter Porker find the will to be Spider-Ham again.

Nick Fury has been infected by nanite versions of Doctor Octopus' Octo-Bots. While the others face off against Doctor Octopus, Spider-Man and Power Man work with Ant-Man to enter Nick Fury's body and get the Octo-Bots out of him.

Craving Mexican food following an entire day training with Hawkeye, Spider-Man, Power Man, and Squirrel Girl sneak out of the Triskelion after hours for late-night burritos. Along the way, they must contend with Mesmero's plot to use the cellular network to brainwash everyone like he did with Batroc the Leaper, Boomerang, Grizzly, and Shocker.

Following Spider-Man's fight with Molten Man, the Inhumans have declared war on Manhattan as Nick Fury blames the exchange student Triton. Spider-Man and Triton discover that Maximus has brainwashed the rest of the Inhuman Royal Family (consisting of Black Bolt, Medusa, Gorgon, Lockjaw and Karnak) and plans to crash Attilan into Manhattan.

Arnim Zola resurfaces and starts replacing Spider-Man's fellow students with synthezoid versions of themselves.

With most of his fellow students replaced with synthezoids, Spider-Man must work with Agent Venom and Rhino to rescue their classmates and defeat Arnim Zola.

Dr. Curt Connors has been turned into Lizard again. This time, he has a bite that turns anyone who is bitten into Lizards. The Triskelion goes under lockdown when Spider-Man's team and the S.H.I.E.L.D. Academy personnel get infected and attack Spider-Man. With help from an item in Nick Fury's office and with the help of Iron Spider, Leo Fitz, and Jemma Simmons, Spider-Man must work on an antidote in order to restore everyone to normal. Meanwhile, Agent Venom and Rhino guard Doctor Octopus' cell during the outbreak just in case he plans any escapes from his cell. Once everyone is cured, Spider-Man witnesses Doctor Octopus and Rhino making off with Agent Venom.

Spider-Man, Iron Spider, Agent Venom, Kid Arachnid, and Scarlet Spider have been looking for signs on where Doctor Octopus is hiding out. Upon Spider-Man and Iron Spider being ambushed by Vulture, they follow him to a nearby island where they are attacked by clones of Sandman. As Spider-Man fights the Sandman clones, Iron Spider stumbles upon a secret laboratory where Doctor Octopus has captured Sandman and cloned him so that he can find the "Ultimate Sandman" that will join the Sinister Six. After Sandman is rescued and Doctor Octopus escapes, Spider-Man allows Sandman to spread out around the Triskelion.

Spider-Man and Agent Venom have been busting villains like Beetle, Grizzly, Shocker, and Shriek where they suspect that they might be candidates for Doctor Octopus' Sinister Six. Arnim Zola recruits Michael Morbius to work on a new symbiote. When Spider-Man, Agent Venom, and Harry Osborn in the Patrioteer armor track them down, they are caught off-guard when they release the Anti-Venom symbiote which possesses Harry and does not have any of the symbiote weaknesses. The resulting battle leaves Agent Venom injured and Harry in a coma.

During a drought, Spider-Man, Iron Spider, Kid Arachnid, and Scarlet Spider answer a distress signal that takes them to an abandoned mall in Queens. They find an empty air-tight room containing Hydro-Man who has a past with Nick Fury. While transporting him to the Triskelion, Iron Spider find that Hydro-Man is not a good guy where the fight with him causes an emergency landing near Aunt May's house. While Spider-Man, Iron Spider, and Kid Arachnid fight Hydro-Man, Scarlet Spider works to protect Aunt May who ends up naming him Ben. Once Hydro-Man is defeated where the resulting battle watered Aunt May's lawn, Spider-Man gets word that the Quinjet carrying Hydro-Man back to his cell was intercepted causing Spider-Man to speculate that Doctor Octopus has gotten Hydro-Man on his side.

Spider-Man faces the culmination of all Doc Ock's evil machinations when the new Sinister Six assaults the Web Warriors and S.H.I.E.L.D. Academy at the Triskelion.

When Doc Ock learns that the key to a device that will retrieve Hydra Island is at Aunt May's house, Spider-Man must fight to protect his family.

When a battered Nova asks for help finding Nick Fury, Spider-Man tracks him to the dangerous ruins of an ancient city.

Spider-Man, having collected all of the shards of the Siege Perilous, returns to Miles Morales' universe and confronts Wolf Spider.

Trick-or-treaters start turning into monsters and Spider-Man, Dr. Strange and Ant-Man must team up to stop Baron Mordo.

Spider-Man must team with the former traitor, Scarlet Spider, to stop Doc Ock from reawakening a secret program designed to create evil duplicates of Spider-Man.

Spider-Man and Scarlet Spider have to infiltrate the sunken Hydra Island so Scarlet can destroy the lab that created him.

Spider-Man puts the Triskelion on lockdown when a mysterious villain begins to take out the heroes one at a time.

Spider-Man house sits on Christmas Eve and is forced to team up with Moon Knight to defend the home from the new Mysterio.

Spidey must track down Ock before he harms Aunt May.

Peter Parker must find a way to stop Doctor Octopus and the Superior Sinister Six from destroying all of the heroes in New York and taking over the world.

Now that the other young heroes have been assembled, Spider-Man must lead them into defending the Tri-Carrier from the Thunderbolts (consisting of Taskmaster, Vulture, and Cloak and Dagger) where they managed to spring Green Goblin, Doctor Octopus, Beetle, and Scorpion from their cells.

The Guardians of the Galaxy land on Earth to repair their ship at the same time ex-Nova Corps member Titus leads the Chitauri into targeting Nova's helmet. Now Spider-Man and Nova must work with the Guardians of the Galaxy to defeat Titus and the Chitauri.