Ushio and Tora centers around the travels and battles of Ushio Aotsuki, who is constantly being stalked and aided by a gigantic, supernatural, and sometimes invisible tiger-like monster named Tora.
Ushio's family maintains a temple in Japan, where 500 years ago, his samurai ancestor battled that same monster to a standstill, and eventually trapped him against a rock using a cursed spear called the "Beast Spear", which grants strength, speed, and endurance to the wielder in exchange for his soul. Ushio accidentally unsealed the cave Tora was trapped in.
Initially, Ushio refuses to remove the spear pinning Tora down (as Tora made the strategic blunder of mentioning that the first thing he would do upon being freed would be to devour Ushio), but Tora's unsealed presence attracts various monsters to the temple. Ushio is forced to free Tora, who would like to eat Ushio, but dares not since Ushio keeps the spear close by. The series focuses on their relationship, interspersed with battles against mythological foes, and with Tora's attempts to grapple with modern life. During the regular battles, Ushio slowly begins to notice that as much as Tora claims to be irredeemable, the demon takes to fighting evil and defending the innocent with more enthusasim than he cares to admit.
The story also includes Ushio's relationships with two girls: the tomboyish Asako Nakamura and the feminine Mayuko Inoue.