Живучи під землею в селі Гіха, Сімон і Каміна мріють про життя на поверхні. Коли їхній дім атакують згори, вони мають активувати таємничу меху Лаґанн і врятувати своє село.

Тепер, коли вони вибралися на поверхню, Сімон і Каміна повинні об'єднатися з Йоко та її селом, щоб перемогти людей-звірів, які їх переслідують.

Каміна і Сімон повинні працювати разом, щоб перемогти нову небезпечну загрозу - Людину-звіра.

Команда Ґуррен має працювати разом з ексцентричними Чорними Сиблінгами, щоб знищити звіролюда на порожній шлунок.

Команда Ґуррена повинна знайти вихід з дивного підземного селища, де ганменам поклоняються як божественним істотам.

Продовжуючи рух до місця збору ганменів, команда Ґуррена опиняється на дивному курорті з гарячими джерелами.

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.

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.

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.

A recap of the story's events from the previous episodes.

During the following seven years, a new civilization rises and prospers under Simon's leadership. However, these peaceful times come to end when the threat mentioned in Lordgenome's last words starts to reveal itself.

To soothe the public opinion, Rossiu overthrows Simon and puts him under arrest. But when the Anti-Spirals launch a large-scale attack on Kamina City, he is left with no option but to let Simon engage the enemy using the Gurren-Lagann, not before resorting to extremes to put him under his control.

As Simon arrives in prison, he unexpectedly meets Viral, who comments on how far he has fallen. Meanwhile, the truth about Rossiu's emergency plan and the consequences for those left behind on Earth are revealed.

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 Gurren-Lagann and the Arc-Gurren join together to form the massive Arc-Gurren-Lagann and stop the Human Annihilation System.

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.

Team Dai-Gurren struggles to escape from the ocean of despair created by the Anti-Spirals without success, until history repeats itself, as another irreplaceable member of the Team sacrifices himself to save the others.

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.