Chitosan nanoparticles have been recognized as a new type of biomaterials for treatment of spinal cord injury (SCI). To develop a novel treatment method targeted delivery injured spinal cord, valproic acid labeled chitosan nanoparticles (VA-CN) were constructed and evaluated in the treatment of SCI. Our results demonstrated that administration of VA-CN significantly promoted the recovery of the function and tissue repair after SCI. Moreover, we found treatment of VA-CN inhibited the reactive astrocytes after SCI. Furthermore, administration of VA-CN enhanced immunoreactions of neuronal related marker NF160, which suggested that VA-CN could promote the neuroprotective function in rats of SCI. The production of IL-1 beta, IL-6 and TNF-alpha were significantly decreased following treatment of VA-CN. Meanwhile, administration of VA-CN effectively improved the blood spinal cord barrier (BSCB) disruption after SCI. Administration of VA-CN could enhance the recovery of neuronal injury, suppress the reactive astrocytes and inflammation, and improve the blood spinal cord barrier disruption after SCI in rats. These results provided a novel and promising therapeutic manner for SCI.