Objective: To demonstrate the effect of medical ozone therapy on the development of epidural fibrosis. Methods: A total of 25 Sprague–Dawley male rats were randomly divided into 3 groups: a control group (L3–L4 laminectomy only), a systemic ozone therapy (SOT) group (L3–L4 laminectomy only + intraperitoneal 15 mL [30 μg/mL] ozone), and a local ozone therapy (LOT) group (L3–L4 laminectomy only + subcutaneous 15 mL [30 μg/mL] ozone). Ozone therapy was administered 4 times on a 3-day interval during the wound-healing process, with the first dose immediately administered after surgery. The effects of ozone therapy on vascular endothelial growth factor, inflammation, and epidural fibrosis between groups were evaluated. Results: Staining with vascular endothelial growth factor was significantly less in the group that received SOT compared with the control group (P = 0.021). When the groups were compared in terms of inflammation, it was found that inflammation was less common in the SOT and LOT groups compared with the control group (SOT vs. control: P = 0.004 and LOT vs. control: P = 0.024), whereas inflammation was found to be significantly less in the SOT group compared with the LOT group (P = 0.008). In the histopathologic evaluation of epidural fibrosis, there was no significant difference between the SOT and LOT groups but less epidural fibrosis was observed in both groups compared to the control group (LOT vs. control: P = 0.037; SOT vs. control: P = 0.018). Conclusions: Medical ozone therapy may be an alternative method that can be used effectively and safely in the prevention of epidural fibrosis after laminectomy.