Spinal cord injury (SCI) can cause irreversible trauma to nervous tissue, leading to permanent damage to the patient's motor and sensory functions. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) can simulate most of the functions of MSCs and are considered an ideal treatment option for SCI. However, the potential mechanism of MSC-EVs treatment for SCI still needs to be explored. We cultured neurons in vitro to investigate the effect of miR-124 on the p62-Keap1-Nrf2 pathway. Besides, MSC-EVs containing miR-124 were injected into a rat spinal cord injury model to observe their neural repair effect. The accumulation of p62 can be reversed by miR-124, which promotes autophagy and alleviates oxidative stress, thereby exerting neuroprotective effects. Rats who received injection of MSC-EVs overexpressing miR-124 after surgery showed higher BBB scores, lower levels of cell apoptosis, and better spinal cord tissue morphology. Our results indicated that miR-124 can stabilize the p62-Keap1-Nrf2 loop, thereby promoting autophagy and alleviating oxidative stress to exert neuroprotective effects. Our research proposes a novel potential target for treating SCI.