Objective To elucidate the mechanism of ozone inhibits angiogenesis in hepatocellular carcinoma via the IL-6/STAT3/VEGFA signaling pathway. Methods Two hepatocellular carcinoma cell lines, HepG2 and LM3, along with human umbilical vein endothelial cells (HUVECs), were utilized. HUVECs were treated with supernatants from both control and ozone-treated hepatocellular carcinoma cell groups, followed by assessment of their proliferative capacity using the CCK-8 assay. The migratory and tube-forming abilities of HUVECs were evaluated through scratch assays and Transwell assays, respectively. Western blot analysis was conducted to assess the expression levels of key proteins within the signaling pathway post-ozone treatment in HepG2 and LM3 cells.Results Treatment with ozone-conditioned medium significantly inhibited proliferation, migration, and tube formation in HUVECs compared to controls (P＜0.05). Following ozone exposure in HepG2 and LM3 cells, Western blot results indicated a marked reduction in IL-6 and p-STAT3 expression within the IL-6/STAT3 signaling pathway relative to controls (P＜0.05), alongside a significant decrease in VEGFA expression (P＜0.05). Conclusion Ozone effectively suppresses HUVECs cells proliferation, migration, and tube formation while downregulating associated protein expressions in liver cancer cells through modulation of the IL-6/STAT3/VEGFA signaling pathway. These findings suggest hat ozone may inhibit angiogenesis in hepatocellular carcinoma by attenuating this specific signaling cascade