Subaru is an ordinary young man with a dream of becoming a Player, a superhuman being who enters mysterious gates to slay creatures and defend humanity. After years of relentless bullying and abuse at the hands of his younger brother Taiga and his peers, a Door of Trials finally appears before Subaru, granting him the power he always wanted. He is selected not as an existing copper, silver, or gold rank, but as the sole Rainbow rank Player, possessing the unique ability to freely manipulate blood. His rise, however, puts him directly in the crosshairs of his brother.

The world faces an additional existential threat beyond the gates: the Sky Clock. This massive timer in the sky is counting down to zero, which would mean the end of the world. When players clear a gate, the remaining time displayed at its entrance is added back to the Sky Clock, pushing back the doomsday countdown. Conversely, failure can cause massive deductions in the remaining time. This creates a high-stakes environment where every gate mission has a direct and measurable impact on humanity's survival timeline.

The story follows Subaru as he struggles to master his newfound powers and climb the ranks. He is soon partnered with a girl named Sōka, and together they challenge increasingly dangerous gates. The early narrative arcs involve Subaru being completely outmatched by the forces within these gates and confronting the immediate danger posed by his brother Taiga, who harbors a deep-seated grudge. After a critical mission where Sōka is mortally wounded, Subaru is forced to make a desperate choice, using a power that revives her but transforms her into a vampiric servant bound to him, which strains his relationships with her sisters.

As the series progresses into its second major narrative phase, a deeper layer is introduced. Subaru gains access to "memories of the future," sent back by his future self. These memories contain revelations about eight impending "calamities" destined to kill his friends. Determined to rewrite fate, Subaru must use this foreknowledge to navigate complex negotiations with powerful entities from the other world and overcome gates of unprecedented difficulty, such as a six-star gate where the first area is an inferno reaching 290 degrees Celsius. This arc shifts the conflict from simple survival to a strategic battle against a predetermined tragic future.

The setting expands from modern-day Japan besieged by dungeons to include other realms entirely: the "different world" beyond the gates where monsters exist, and the "void world" where the masters of the trials reside. A key figure is the "true ancestor" Vanquish, a high-ranking vampire lord from the different world who now resides in the void world and is the source of Subaru's power. The reasons these powerful beings lend their strength to humanity remain a central mystery, with hints that the Player system itself has hidden costs and that a more significant threat may lie beyond the final gate of the Sky Clock itself.