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. Because frequent earthquakes damage infrastructure, the villages must constantly extend deeper into the earth—individuals relegated to this task are known as "diggers".
Jeeha 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. Fortuitously, Kamina's punishment is interrupted by the collapse of the ceiling over Jeeha Village, as an enormous mecha falls into the cavern. A girl 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 help Yoko and her village destroy three more Gunmen of which Kamina takes one for himself, naming it "Gurren"(meaning "crimson"). 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 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")-Gurren Brigade'.
Before a final battle with their old enemy, Viral, the Dai-Gurren Brigade plans to hijack a giant Gunmen with which the Beastmen have previously attacked them. 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 to be distracted during the final battle, ultimately contributing to a great tragedy.
The Dai-Gurren Brigade ultimately defeats the Human Eradication Army, causing the arrival of Nia, the mysterious "daughter" of the Beastmen leader Lordgenome, and the repopulation of Earth's surface.
The second half of the series takes place seven years later. Led by Simon and members of Dai-Gurren Brigade, mankind has become prosperous. Though all seems well, once one million humans have repopulated the surface, two new conflicts arise with the arrival of the Anti-Spirals, including Nia's sudden "transformation" into their messenger, and the activation of the Moon, which the Anti-Spirals have actually transformed into a Gunmen to fall into and destroy the Earth once the million-person threshold was broken. Simon, along with the rest of the Brigade and his reformed enemy Viral, then leads the battle to defeat the Anti-Spirals and save Earth.