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.

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.

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.

Team Dai-Gurren are now on their way to Beastmen's capital city, Teppelin but there's a vast ocean in their way. The only way for them to get across is for the Dai-Gurren to be modified, so while they wait everyone goes to chill out at the beach. Once preparations are complete, the Great Gurren Brigade begins their cruise, but there's an ambush waiting for them.

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.

Guided by Simon and Nia's feelings for each other, Team Dai-Gurren break through dimensions in search for the Anti-Spirals' homeworld. But after falling into the enemy's trap, they end up losing some of their most precious members, due to its vicious offensive.

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.