The story follows Michael Steven Donovan, nicknamed "Blueberry", a name he chooses when fleeing from his Southern enemies (which is inspired when he looks at a blueberry bush), starting with his adventures as a lieutenant in the United States Cavalry shortly after the American Civil War.
Donovan is the son of a rich Southern farmer and starts as a dedicated racist. He is framed for a murder he did not commit, flees and is saved by an African-American. He becomes an enemy of discrimination of all kinds, fights against the Confederates, and tries to protect the rights of Native Americans.