The single-atom attracts growing interests in various fields and provides a new strategy for tumor therapy by inspiring chemodynamic-photothermal therapy (CPT) effects owing to its excellent catalytic properties. We synthesize the Folic acid@single atomic manganese (Mn) nanoparticles (FA@SAMn NPs) with mesoporous carbon sphere structure by the coordination aided polymerization assembly method. Antitumor therapeutic effect studies were carried out in vitro and in vivo. This hierarchical nanostructure possesses a high surface area, large pore, and rich N that provide higher catalytic activity, and it also exhibits excellent activity and stability in the oxygen reduction reaction. With its accumulation in the specific tumor microenvironment, the FA@SAMn NPs could generate reactive oxygen species (ROS), which would mediate a series of 4 T1 cell damage and inhibit tumor propagation (56% mortality rate). Moreover, the FA@SAMn NPs possess an excellent photothermal effect under near infrared-II (NIR-II) laser irradiation. This leads to a local hyperthermia situation in the tumor area and contributes to tumor inhibition (91% mortality rate). In sum, FA@SAMn catalysts effectively suppressed tumor growth and significantly increased the survival time. This work aims to provide new potential single-atom-coordinated carbon networks that possess efficient biocatalytic sites and photothermal effects, inspiring a series of advances in ROS and photothermal-related biological applications across broad biomedical fields.