"Hand Shakers" is set in a fictional version of Osaka, where individuals known as "Hand Shakers" form pairs to battle for a chance to meet and challenge a deity known as "God." These pairs, bound by a physical connection, wield supernatural weapons called "Nimrods," which manifest through their synchronized willpower. The series centers on Tazuna Takatsuki, a high school student with a knack for repairing machinery, and Koyori Akutagawa, a mysterious girl he encounters in a hospital. After forming a pact, they become Hand Shakers, thrust into a dangerous tournament where they must defeat other pairs to ascend to God.

The narrative explores the dynamics of the Hand Shakers' relationships, emphasizing trust and emotional bonds as crucial elements for success in battle. Each pair faces unique challenges, both external and internal, as they navigate the high-stakes competition. Tazuna and Koyori's journey is marked by their growing connection and the revelation of Koyori's fragile health, which adds urgency to their quest. The series introduces a variety of rival pairs, each with distinct motivations and backstories, contributing to the overarching conflict.

Themes of perseverance, sacrifice, and the consequences of ambition are woven throughout the story. The battles are intense and visually driven, with the Nimrods reflecting the personalities and emotions of their wielders. As Tazuna and Koyori progress, they uncover deeper layers of the Hand Shakers' world, including the enigmatic organization Ziggurat, which oversees the battles and maintains the rules of the tournament. The series builds toward a climactic confrontation with God, exploring the moral and emotional toll of the characters' choices.