Team Dai-Gurren falls into a trap set by the third member of the Four Divine Generals, Guame. The Team is taken captive and stored underground to await execution. While digging an escape path, Simon finally understands Kamina's last words to him and after having a discussion with Guame, Nia finds out the reason why she was thrown away.

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.

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.

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.