Noriko Takaya has spent barely had a month at a training school for giant robots. The school announces they are going to select two candidates to go to the Exelion spaceship for the real missions to fight against an invading mech army. One of the choices is obviously the beautiful and leading senior Kazumi Amano, but somehow Noriko is selected for the second spot! The other girls get jealous that Noriko got the spot, suspecting it's because she was the daughter of the Admiral in a previous mission. School rival Reiko Kashihara feels that's totally wrong, and challenges Noriko to a duel.

Noriko and Kazumi arrive at the space fleet led by the space battleship Exelion. The girls get introduced to a hot shot female fighter named Jung Freud. During one of their mech training sessions, Jung spars with Kazumi, and end up in a part of the station where they discover one of the mechs of their enemy. Later on, Noriko and Kazumi are sent to partake in a special mission to investigate an object traveling at near light speed. With the laws of quantum physics and time dilation, the mission that would normally take just a few minutes will span several months. But they discover the object is the Lexion, the ship that Noriko's dad used to command.

The Exelion prepares to jump through hyperspace. All the girls and guys are confined to their quarters during the mission, but Noriko loses a dare game, and has to wander off in the dark. She is surprised when a person shows up, but it turns out to be a charming guy named Toren Smith, who befriends Noriko. They get into some minor trouble for being out, and as punishment, they have to polish the lenses for the laser cannon array. But then the Exelion gets a surprise fly-by by the enemy. The fleet goes after them for a large battle at Leaf 64. Toren offers to be Noriko's partner for the next battle, since she has fallen out of favor from Kazumi. But trouble arises as they get overwhelmed by the sweeping enemy.

The fleet advisor tells Captain that the aliens are going to attack Earth. Coach has been training Noriko, but Jung wants to test Noriko by challenging her to a duel. Noriko is still shaken from the death of her comrade and breaks down when they are outside. As the fleet is preparing to jump back to Earth, hoping to hide their trail in subspace, they are suddenly attacked by the aliens and everyone scrambles for their mechs. Noriko is benched for the battle. Things look bleak as most of the defense forces are wiped out, but Noriko manages to get out of her rut and moves to pilot the force's super prototype mech called Gunbuster.

Kazumi and Noriko return to Earth for their high school graduation. Even though they are still teenagers after all these months in space, the Earth has aged ten years. Noriko meets up with her friend Kimiko, who now has a daughter. The Earth's forces discover that a massive number of alien spaceships are converging into the solar system. Coach has a strategy that involves creating a miniature black hole around Jupiter 2, but he will need Kazumi and Noriko to work together to pilot Gunbuster in order to put his plan into operation. However, Kazumi is having second thoughts as she's fallen in love with Coach and knows of his health situation.

Fifteen years later, Kazumi is called to another mission, to detonate a black hole bomb in the enemy's home galaxy. She joins Noriko and Jung as they pilot the Gunbusters to their final destiny that could mean the "extinction or survival of the human race."

Nono, a young girl from the country, moves to the big city in order to achieve her dream: becoming a space pilot!

Mars' Space Force isn't happy about space monsters showing up on their doorstep, and they blame the Fraternity.

Tycho wrecks her Buster Machine, ruining her chance to reach top. Not to worry--there's another Buster Machine in the works.

Nono's despair grows as her certainty that she'll get a Buster Machine fades.

After the Titan incident, the world has changed. Topless are a disease, and humanity's last hope for salvation is the least likely person in the Sol System.

With the survival of humanity itself at stake, one desperate plan remains: the sacrifice of the Earth, to strike at the beast! But where is Buster Machine #7?