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The story begins in July 2008, during a time when humankind is faced with the threat of extinction. A devastating war fought between two major nations with ultra-magnetic weapons far greater than anything seen earlier brings about total chaos and destruction throughout the world, resulting in several earthquakes and tidal waves, the earth thrown off its axis, its crust being rocked by massive movements, and the five continents being torn completely apart and sinking deep below the sea.

Gurren Lagann takes place in a fictional future where Earth is ruled by the Spiral King, Lordgenome, who forces mankind to live in isolated subterranean villages. These villages have no contact with the surface world or other villages, and are under constant threat of earthquakes.

16 years after the "Law for Public Order and Morals in Healthy Child-Raising" banned coarse language in the country, Tanukichi Okuma enrolls in the country's leading elite public morals school and is soon invited into the Anti-Societal Organization (SOX) by its founder, Ayame Kajou. As a member blackmailed into joining by Ayame, Tanukichi ends up taking part in obscene acts of terrorism against the talented student council president Anna (for whom Tanukichi has a crush on).

Yukiteru Amano (or Yuki) is a loner who never really interact with people and prefers writing a diary on his cell phone with his only companion being an imaginary friend named Deus Ex Machina, the God of Time and Space. However, Yuki soon learns that Deus is not a figment of his imagination but real when Deus makes him a participant in a battle royale with eleven others.