Spinal cord injury (SCI) is a devastating condition that results in the loss of sensory and motor functions. The complex pathogenesis of SCI contributes to the limited availability of effective therapies. Two major factors exacerbating secondary injury in SCI are neuronal ferroptosis and microglial inflammatory polarization. Tanshinone IIA (TSIIA) has demonstrated a significant anti-ferroptosis effect by inhibiting lipid peroxidation, while tetramethylpyrazine (TMP) exhibits remarkable anti-inflammatory properties by promoting the shift of microglial polarization from the M1 to the M2 phenotype. However, most drugs currently under development primarily target a single aspect of this multifaceted condition, which is insufficient for comprehensive treatment. Selenium nanoparticles have emerged as a promising therapeutic strategy due to their ability to encapsulate various agents, effectively targeting diverse pathophysiological mechanisms while offering favorable water solubility and low toxicity. In this study, we developed a novel nanocarrier functionalized with astragalus polysaccharide (APS) and loaded with TSIIA and TMP. Results from both and studies indicate that TSIIA/TMP/APS@Se NPs possess anti-ferroptosis properties and can regulate microglial polarization, potentially enhancing functional recovery following SCI. In summary, this study presents a promising alternative strategy for treating SCI, highlighting its significant potential for future clinical applications.