Silver nanoparticles (AgNPs) possess anti-inflammatory activities and have been widely deployed for promoting tissue repair. Here we explored the efficacy of AgNPs on functional recovery after spinal cord injury (SCI). Our data indicated that, in a SCI rat model, local AgNPs delivery could significantly recover locomotor function and exert neuroprotection through reducing of pro-inflammatory M1 survival. Furthermore, in comparison with Raw 264.7-derived M0 and M2, a higher level of AgNPs uptake and more pronounced cytotoxicity were detected in M1. RNA-seq analysis revealed the apoptotic genes in M1 were upregulated by AgNPs, whereas in M0 and M2, pro-apoptotic genes were downregulated and PI3k-Akt pathway signaling pathway was upregulated. Moreover, AgNPs treatment preferentially reduced cell viability of human monocyte-derived M1 comparing to M2, supporting its effect on M1 in human. Overall, our findings reveal AgNPs could suppress M1 activity and imply its therapeutic potential in promoting post-SCI motor recovery.