Gurren Lagann takes place in a fictional future in which human beings have been forced under Earth's surface and live in isolated subterranean civilizations. These "villages" have no contact with the surface world or other villages.
Giha Village, one of the underground villages, regularly experiences earthquakes; because these earthquakes damage infrastructure, the village must constantly extend deeper into the earth—individuals relegated to this task are known as "Diggers". Giha Village is the home of Simon, a fourteen-year-old digger who was orphaned when his parents were killed in an earthquake. Although Simon is respected by the village elders as the best of the diggers, he is ostracized by his peers. Simon discovers a special drill key deep in the ground and is soon recruited by an eccentric fellow orphan named Kamina into his group, the "Gurren Brigade". Kamina dreams of the surface world, which he once visited as a child, though he had to return home as he was too young to survive there.
After a failed attempt at reaching the surface, Kamina is jailed by the village elder. Simon resumes digging, only to discover "a big face" deep in his tunnel. As he excitedly fetches Kamina to show him the discovery, Simon is also caught by the village elder. Kamina's punishment is interrupted by the collapse of the ceiling over Giha Village, as an enormous mecha falls into the cavern. A woman named Yoko appears and tries to repel the machine with a large rifle. Simon takes Kamina and Yoko to the "big face" he found earlier and discovers that the small drill key can be used to activate it. Named "Lagann", he uses it to destroy the invading mecha and effectively break through to the surface.
Once on the surface, Simon and Kamina discover there are more large mechas known as "Gunmen" (piloted by "Beastmen") that terrorize the surface dwellers during the day. Simon and Kamina volunteer to help Yoko and her village; during the ensuing battle Kamina captures a gunmen and names it "Gurren" (meaning "crimson lotus"). Eventually, Simon and Kamina decide to embark on a journey to end the constant struggle between the Beastmen and humans, and are initially accompanied by Yoko and Leeron, a mechanic from Yoko's village. As they head out to find the headquarters of the Beastmen's Human Eradication Army, the group encounters various Beastmen warriors including the vicious beastman Viral. Along the way, Simon and the others are joined by more humans, including the "Black Siblings", led by Kittan, and Rossiu, a strict young man from an underground village, to form the "Dai (meaning "large" or "great") Team Gurren".
Team Dai-Gurren form a plan to hijack the giant fortress Gunmen the Beastmen have been using as a local base of operations. Kamina plans for Simon to steal the Gunmen using the Lagann. Later that night, while Kamina is talking, Yoko kisses him, and he reciprocates. Unseen, Simon follows Yoko and witnesses the event. This causes Simon a significant amount of psychological trauma and consequently he is distracted during the final battle, contributing to the death of his "brother", Kamina.
Team Dai-Gurren continue on, adding the daughter of the king of the Beastmen, Nia, to their ranks, and encountering and defeating the remaining generals of the Human Eradication Army. They eventually reach the capital of the Beastmen and defeat the Beastmen's king, Lordgenome. However, in doing so Simon learns of the power of the Spiral, and the destruction that it could cause. Lordgenome was once a spiral warrior who fought against the "Anti-Spirals" and failed. To preserve human kind, he forced all humans to live underground and keep their population to a minimum so they would not alert the anti-spirals to their presence.
The second half of the series takes place seven years later. Led by Simon and members of Team Dai-Gurren, mankind has become prosperous. Though all seems well, once one million humans have repopulated the surface, the anti-spirals arrive and begin attacking the humans, and Nia is suddenly transformed into their messenger. The conflict escalates, causing infighting within the Dai-Gurren members in the new capital government, and panic in the world's population when it is learned that the anti-spirals have begun their plan to eradicate all life by crashing the moon into the earth. Simon, along with the rest of the Team and his old rival, Viral, lead the battle to defeat the Anti-Spirals and save Earth, first by averting the moon disaster, and then by confronting the anti-spirals in their home pocket dimension.
However, in destroying the Anti-Spiral, Nia's fate is sealed. She holds onto life long enough to marry Simon before crumbling to dust. Simon then passes his core drill on to a new generation and spends the rest of his life wandering the earth as a nameless vagrant, while the human race begins to contact its fellow Spiral races throughout the galaxy.
