"Knights of Sidonia" is a science fiction manga series set in a distant future where humanity has fled Earth after its destruction by an alien species known as the Gauna. The remnants of humanity reside aboard massive seed ships, with the Sidonia being one of the last surviving vessels. The story centers on Nagate Tanikaze, a young man who has lived in isolation deep within the ship, trained in piloting mechs called Gardes by his grandfather. When he emerges, he discovers a society that has evolved significantly, with humans now capable of photosynthesis and some individuals genetically engineered to be genderless.

Nagate is thrust into the forefront of Sidonia's defense when the Gauna reappear, threatening the ship's survival. He becomes a key pilot in the battle against these enigmatic and nearly indestructible aliens. The Gauna are amorphous, shape-shifting beings that mimic their prey, making them formidable opponents. Sidonia's military relies on advanced Gardes and a unique weapon called the "Higgs Cannon" to combat them. Nagate's natural piloting skills and adaptability quickly make him a crucial asset in the ongoing war.

The narrative explores the complexities of life aboard Sidonia, including its rigid social hierarchy, political intrigue, and the ethical dilemmas of genetic engineering. Key characters include Izana Shinatose, a genderless individual who forms a close bond with Nagate; Yuhata Midorikawa, a strategic officer who plays a pivotal role in military operations; and Kunato Norio, a rival pilot whose jealousy and ambition create tension. The series also delves into the mystery of the Gauna, their origins, and their connection to humanity.

As the story progresses, Nagate and his allies face increasingly dire threats, including internal conflicts and the revelation of Sidonia's true purpose. The manga balances intense mecha battles with themes of survival, identity, and the resilience of humanity in the face of extinction. The narrative builds toward a climactic confrontation with the Gauna, revealing deeper layers of the conflict and the sacrifices required to ensure Sidonia's survival.