In spite of their defeat, the remnant factions of the Taipingtao Revolution continue to resist, plunging China into a seemingly never-ending war. Moreover, the negative emotions left behind by the rebellion's massive death toll begin to form miasma—giving birth to malignant beings called the "wangliang." These creatures can possess humans and turn them into horrifying demons, thus bringing about more deaths and miasma and spinning a vicious cycle that inflicts further despair upon the land. As a countermeasure, the immortal deities known as the "Tianyuan" select certain individuals to be "Hunters." Accompanying them are the "Guizhan," specialists created by the Tianyuan who can absorb miasma and transform into demons themselves, acting as indispensable weapons against the wangliang. After a tragic accident involving an out-of-control Guizhan causes the disbandment of the Sixth Hunter Unit, the Tianyuan designate three promising Hunters—namely Ji Ying, Qiao Xun, and Yan Ding—to reform the group. However, for an unknown reason, the Tianyuan also appoint Xiao Ling—the young Guizhan responsible for the former unit's downfall—to fight alongside the trio. Despite growing tensions, the members of the revived team must settle their differences and collectively use their abilities to attain victory against the common enemy.

Gensou Sangokushi: Tengen Reishinki is based on the Taiwanese role-playing video game series Fantasia Sango by UserJoy Technology.