Eiji Mikami, the so-called "Wolf of Shinjuku", is a 36-year-old police detective at the Central Shinjuku Station known for his own distinct brand of justice. After an undercover agent investigating a gun smuggling ring is discovered and killed, a deal goes bad and illicit weaponry winds up all over the city. Crime is on the rise, and it's up to Eiji and the Shinjuku Police to recover the stolen weapons.

Shinjuku no Ōkami is an open-world action game similar to Grand Theft Auto. The game is set in a fictionalized version of the Shinjuku ward of Tokyo, Japan, with the player taking control of the Dirty Harry-esque detective Eiji Mikami. The story is broken into missions, which usually involve catching and arresting criminals. However, he must be careful to keep innocent citizens out of harm's way; if he harms too many innocents, his badge will be revoked, causing an immediate game over. However, he can return to the station between missions to write apology letters and repair his reputation.

Eiji has a wide range of abilities, ranging from standard punches and kicks to more elaborate moves like jump-kicks, elbow drops, and several ways to arrest, intimidate, or interrogate criminals. He can wield a range of weapons, including both pistols and large explosives, and can also ride bicycles and drive cars to travel around the city.

There are a large variety of different activities that Eiji can participate in. He can patrol the streets looking for criminals to arrest, go to the station to rest or write apology letters via a button-mashing mini-game, visit stores to buy food and clothing, get haircuts, visit pachinko halls and mahjong clubs to gamble, or even visit a batting center and hit a few home runs.

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