In this work, we explored the role and mechanism of sea buckthorn oil in reducing radiation-induced skin damage. The radiation-induced rat skin injury model was established using strontium-90. Rats were treated with sea buckthorn oil twice a day postirradiation, and skin damage was observed at different times and evaluated using an injury score. Skin pathological changes were observed using hematoxylin and eosin (H&E) staining. Western blotting and immunohistochemistry were used to detect the expression of vascular growth and pathway proteins. ELISA was used to detect the secretion level of inflammatory factors. Immunohistochemistry was used to detect macrophage polarization marker proteins. We found that sea buckthorn oil can alleviate radiation-induced skin damage, accelerate skin vascular regeneration, and promote the up-regulation of vascular endothelial growth factor (VEGF) and its receptor (VEGFR). These results demonstrate the beneficial effects of sea buckthorn oil on radiation-induced skin damage. Furthermore, the levels of IL-1β and TNF-α in the sea buckthorn oil treatment group were significantly lower than those in the control group, while the levels of IL-4 and IL10 were significantly higher (P < 0.05). CD206 expression also increased in the sea buckthorn oil treatment group, while CD16 expression decreased compared to the control group (P < 0.05). Western blotting showed that PI3K, Akt and ERK expression increased in the sea buckthorn oil treatment group (P < 0.05). The beneficial effect of sea buckthorn oil in reducing the inflammatory response in irradiated rats was diminished when they were treated with PI3K inhibitor. We conclude that sea buckthorn oil may regulate macrophage M2 polarization by increasing the PI3K-Akt-ERK signaling pathway, thereby inhibiting the inflammatory response and promoting skin vascular regeneration to prevent and treat radiation-induced skin damage.