Spinal cord injury (SCI) remains the most common cause of paralysis, and there are no effective therapies for SCI patients. Neural stem cell (NSC)-derived exosomes can attenuate apoptosis and neuroinflammation after traumatic spinal cord injury, but the mechanisms underlying these effects remain unclear. Here, we examined the efficacy of miRNAs isolated from exosomes as treatments for SCI and characterized their mechanisms of action. Furthermore, we evaluated the effects of exosomes formed in the presence of insulin growth factor-1 (IFG-1, IGF-Exo), which promotes neural proliferation and regeneration, as well as normal exosomes (Nor-Exo) and compared control and H2O2-treated groups both in vitro and in vivo. Using microRNA sequencing and qRT-PCR, we identified miR-219a-2-3p, levels of which were higher in the IGF-Exo than Nor-Exo group and played crucial anti-inflammatory and anti-apoptosis roles. Additional experiments revealed that IGF-Exo inhibits YY1 expression through up-regulation of miR-219a-2-3p. This in turn inhibits the NF-κB pathway, partly inhibiting neuroinflammation and promoting the neuroprotective effects after SCI.