Final Fantasy X-2 begins as Yuna, Rikku and Paine recover Yuna's stolen Garment Grid from the Leblanc Syndicate in the first of several encounters in which they vie for spheres. The game is punctuated by a narration of Yuna addressing Tidus, as though she is recounting the events of the game to him as they occur in a style reminiscent of Tidus' own narration in Final Fantasy X.

Although Yuna's quest is to find clues that may lead her to Tidus, much of the storyline of the game follows the clash of the factions that have established themselves in the time since the coming of the Eternal Calm in Final Fantasy X, and the uncovering of hidden legacies from Spira's ancient history.

As the game progresses, the hostilities between the Youth League and New Yevon build to a head. In the meantime, the Gullwings discover an ancient sphere containing images of an enormous machina weapon called "Vegnagun" that was secretly buried beneath the city of Bevelle. The weapon has enough power to threaten all of Spira, and, moreover, it is revealed that Vegnagun is unable to distinguish friend from foe once activated.