Ten years ago, a Martian expedition crew brought a mysterious artifact nicknamed the "Pandora Box" to Earth. The artifact was activated during a national conference which caused a massive catastrophe in the form of a Skywall which split Japan into three regions: Seito in the west, Hokuto in the north, and Touto in the east, with each region holding onto the fragments of the Pandora Box. In the present day, a genius physicist named Sento Kiryū is hired by the government-funded Touto Institute of Advanced Matter Physics in uncovering the Pandora Box's secrets. But Sento, having no memory of his past other than being held captive by the mysterious Night Rogue of the Faust organization, secretly moonlights on the side as Kamen Rider Build to fight the Smash monsters created from victims of Faust's experiments. Aided by cafe owner Sōichi Isurugi and his daughter Misora, who can purify Smash elements, Sento also befriended a framed fugitive named Ryūga Banjō who escaped while being experimented on by Faust and who eventually gained the ability to transform into Kamen Rider Cross-Z.