Spinal cord ischemia-reperfusion injury (IR) is a terrible non-traumatic injury that occurs after abdominal aortic occlusion and causes serious damage to neurological function. Several treatment strategies have been suggested for IR, but they were not unable to effectively improve these conditions. Herein we investigated whether exosomes derived from human placental mesenchymal stem cells (hpMSCs-Exos) in combination with hyperbaric oxygen (HBO) could alleviate injury and promote recovery in IR rats. Eighty male Sprague-Dawley rats were randomly allocated into five equal groups. In addition to the control group that only underwent laparotomy, IR animals were planned into four groups as follows: IR group; IR-Exos group; IR-HBO group; and IR-Exos + HBO group. Neurological function evaluated before, 6 h, 12 h, 24 h, and 48 h after injury. After the last neurological evaluation, tissue samples were obtained for stereological, biochemical, and molecular assessments. Our results indicated that the neurological function scores (MDI), the numerical density of neurons, the levels of antioxidative factors (GSH, SOD, and CAT), and anti-inflammatory cytokine (IL-10) were considerably greater in treatment groups than in the IR group, and these changes were more obvious in the IR-Exos + HBO ones. This is while the numerical density of glial cells, the levels of an oxidative factor (MDA) and inflammatory cytokines (IL-1β, TNF-α, and IL-18), as well as the expression of an apoptotic protein (caspase-3) were meaningfully decreased in treatment groups, especially IR-Exos + HBO group, compared to the IR group. Generally, it was found that co-administration of hpMSCs-Exos and HBO has synergistic neuroprotective effects in the rats undergoing IR.