Previously, our group showed that mianserin, an atypical antidepressant, exerts stronger cytotoxicity against liver cancer cells than normal hepatocytes, supporting its potential application as a therapeutic agent for liver cancer. However, the anti-tumor effects of mianserin and its mechanisms are yet to be established. In this study, we explored the inhibitory effects and mechanisms of mianserin and evaluated its efficacy in combination with sorafenib against liver cancer cells. Effects on cell viability were assessed via MTT and flow cytometry assays and antitumor activity evaluated using a xenograft model. Changes in the expression and distribution of specific proteins within cells were examined via immunoblot assay. Our results indicate that mianserin exerts cytotoxic effects by inhibiting cell viability through suppression of proliferation and induction of apoptosis. Therapeutic effects of mianserin were validated via intratumoral injection in the xenograft model. Mechanistically, our data indicate that mianserin-induced cytosolic HSP60 translocates to cell surface and participates in the downregulation of CCR9, leading to inactivation of the AKT-(β-catenin/NFκB) signaling pathway. Combination treatment with mianserin and sorafenib induced significant synergistic effects on cell viability, apoptosis, and tumor growth in both parental and sorafenib-resistant liver cancer cells. This study is the first to demonstrated that mianserin effectively limits the growth of liver cancer by downregulating CCR9, in turn, inactivating the AKT-(β-catenin/NFκB) pathway. Both and experiments highlight mianserin's potential as an adjuvant therapy to sorafenib, offering a promising strategy to overcome current challenges in liver cancer treatment.