Abstract This study investigated the inhibitory effect of Ononin on hepatocellular carcinoma (HCC) and to elucidate its molecular mechanisms. CCK-8, EdU, colony formation, and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. Western blotting and RT-qPCR analyzed protein and gene expression. Rescue experiments were conducted using EGFR knockdown, overexpression, and IGF-1. A xenograft mouse model evaluated the in vivo efficacy.