Like a Dragon: Ishin! is a standalone spinoff of the Like a Dragon series set in 1860s Japan during the Bakumatsu Era at the end of the Edo Period. Japan is thrown into turmoil after the arrival of Western ships, galvanizing the imperialist ideals of the Shishi, who wish to rebuild the nation around the Emperor by overthrowing the Bakufu and expelling foreigners.

The game features an open world focusing on a powerful feudal domain and castle town in east Japan, Tosa, and Japans capital city at the time, Kyo. Kyo is divided into several key areas: the hospitality district Fushimi, the red light district Gion, the bustling Rakunai, the deserted Rakugai, and the perilous Mukurogai. The Shinsengumi (a notorious police force organized by the Bakufu) is headquartered in Kyo, where the majority of the game takes place.