Excessive accumulations of reactive oxygen species (ROS) and M1 macrophages are closely associated with the complex pathogenesis of spinal cord injury (SCI). Thus, therapeutics that synergistically exert the elimination of ROS and repolarization of pro-inflammation macrophages are gaining increasing notice. We developed a prussian blue-based nanoflower (KPBF) with near-infrared (NIR) photothermal and antioxidant properties. The KPBF's biofunctions were similar to those of other antioxidant enzymes, such as catalase and superoxide dismutase, which are capable of reducing ROS. With NIR irradiation, KPBF efficiently heated the injured spinal cord lesion. By modifying the CKLVFFAED peptide, KPBF remarkably penetrated through the blood–spinal cord barrier (BSCB) into the local lesion. Moreover, KPBF repolarized M1 macrophages and alleviated neuroinflammation in SCI mice. Overall, KPBF presented a universal nanotherapeutic system with immunoregulation and antioxidant activities for acute SCI recovery.