Arsenic trioxide (ATO) is involved in a variety of biological processes of hepatocellular carcinoma (HCC) cells, including apoptosis induction, proliferation inhibition, invasion and metastasis inhibition, and tumor stem cell inhibition. ATO has a variety of therapeutic approaches in the treatment of HCC, mainly including single drug therapy, combined local therapy, combined systemic therapy, and so on. Further research on the anti-cancer mechanism and clinical application of ATO is expected to provide new ideas for the treatment of liver cancer.