Ushio to Tora centers around the travails and battles of Ushio Aotsuki, who is constantly being stalked and aided by a gigantic, supernatural and sometimes invisible tiger-like monster.

Ushio's family maintains a Shinto temple in Japan, where ~500 years ago, his samurai ancestor battled that same tiger to a standstill, and eventually trapped him against a rock using a blessed spear called the "Beast Spear," which in addition to its intrinsic formidability as a weapon, can also endow its wielder with the martial ability of the ancestor who originally wielded it.

Ushio accidentally unsealed the cave Tora was trapped in. Initially, Ushio refuses to remove the spear pinning Tora down, but Tora's unsealed presence summons various monsters who wish to fight him, and by extension Ushio. 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.