Sertraline inhibited HCC cell proliferation and colony formation in vitroDownregulated AKT/mTOR signaling, reducing p‐AKT and p‐mTOR expressionReduced Ki67 expression and tumor growth in xenograft and DEN/CCl4‐induced liver cancer modelsSynergized with sorafenib, enhancing cytotoxicity in HepG2 and Huh7.5.1 cells (CI < 1)Combination treatment induced apoptosis and was well tolerated in normal liver cells and mice. Here, MKI67 is linked to hepatocellular carcinoma.