Hand Shakers centers on those who receive the Revelation of Babel, a calling that forces them through many battles and trials. By grasping the hand of a special partner, these Hand Shakers transport themselves to Ziggurat, an alternate dimension where time no longer exists. Every pair must battle other Hand Shakers there for the right to meet God, who rewards the victors by granting a single wish.
Tazuna Takatsuki, a high school student with a talent for fixing things, has no connection to that world until a repair request from Professor Makihara draws him to a nearby university. In one of its rooms he finds Koyori Akutagawa, a bedridden girl whose face and fragility remind him of his deceased sister Musubu. Tazuna still remembers Musubu's dying wish that he never let go of her hand, and that memory shapes the choice he makes when he reaches out to Koyori.
The instant Tazuna grasps Koyori's hand, he awakens his power as a Hand Shaker and becomes her partner. Koyori's life is directly tied to that status: if Tazuna ever lets go of her hand, she will die. Meeting God becomes their only hope of saving her, but first the two must learn how to make their unique powers mesh together, overcome the Hand Shakers standing in their way, and survive the trials of Ziggurat long enough to make their wish come true.