Living underground in Giha Village, Simon and Kamina dream of a life on the surface. When their home is invaded from above, it is up to them to activate the mysterious mecha Lagann and save their village.

Now that they've made it to the surface, Simon and Kamina must join together with Yoko and her village to defeat the Beastmen pursuing them.

Team Gurren must find their way out of a strange underground village where Gunmen are worshipped as divine beings.

Continuing to the Gunmen rallying point, Team Gurren finds themselves on a strange hot springs getaway.

Thymilph, one of the Four Divine Generals of the mysterious Spiral King, arrives to support Viral's Enki, with the massive mobile Gunmen fortress, the Dai-Ganzan. Kamina and Simon pilot the Gurren-Lagann against seemingly overwhelming odds.

Having temporarily stalled Viral and Thymilph in the last skirmish, the Team Gurren and their newly arrived allies join forces as "Team Dai-Gurren" and launch a decisive strike against the regrouping Gunmen force.

Team Dai-Gurren managed to take control of the enemy fortress, but is still mourning the death of one of their own, especially Simon. After falling off a cliff, he notices a Gunman throw a capsule into a deep valley. Simon inspects it and finds he is able to open it with the same drill key he uses to pilot Lagann, and inside is a young human girl named Nia, but their introduction is cut short when an enemy Gunman appears.

Nia true identity is revealed, as she flaunts her authority to get rid of another one of the Four Divine Generals, Adiane. The members of the Great Gurren Brigade are now suspicious of Nia and her true intentions, but she is only concerned about the depressed Simon. Adiane later returns to finish them all off, with Lordgenome's blessing.

Trying to do her part in Team Dai-Gurren, Nia decides to become a cook, but just before the crew have a taste of her dishes, Cytomander, the fourth member of the Divine Generals, launches an aerial attack on the Dai-Gurren. Simon leads the counter-attack on the Gurren-Lagann, this time accompanied by Yoko, who replaces a sick Rossiu.

At last, Team Dai-Gurren arrives at the outskirts of Teppelin, but before aiming to the city, they must face a combined full-scale attack of Cytomander and Guame's forces.

The last of the Divine Generals fall, and the city of Teppelin collapses, revealing a Gunman of gigantic proportions. Simon and Nia struggle to pass through it in order to confront her father, the Spiral King himself.

One year earlier, Yoko starts working as a schoolteacher on an island until she learns of the situation at Teppelin and returns to break Simon free. Once again reunited, Simon and the members of Team Dai-Gurren launch themselves into space to protect the Arc-Gurren from the enemy forces, now accompanied by Viral as co-pilot of the Gurren-Lagann.

The members of Team Dai-Gurren make their preparations for the imminent war against the Anti-Spirals, but Rossiu is missing. However, when Kinon tells Simon about what he really intends to do, both start to look desperately for him.

After finally transforming their flagship into the Super Galactic Gurren-Lagann, Simon and his friends successfully fight back against the enemy. When their enemy starts to use their own memories and desires against them, Kamina reappears to help.

At last, Simon and Nia are reunited, and by combining the power of its members, Team Dai-Gurren creates the galaxy-sized Tengen Toppa Gurren-Lagann, and engage the Anti-Spiral threat in a decisive battle to determine the fate of the universe.