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Hepatocellular carcinoma (HCC) is associated with high mortality due to late diagnosis, recurrence, and limited therapeutic options. Thus, there is an urgent need for novel treatment approaches and new therapeutic targets. Cardiotoxicity resulting from anticancer therapies has become increasingly prominent, leading to a higher risk of cardiovascular diseases among cancer survivors. In our study, through a drug library screening, we identified that the cardiovascular therapeutic agent nebivolol exerts antitumor effects against HCC both in vivo and in vitro. Mechanistically, nebivolol suppressed HCC progression by downregulating RHOQ independently of β₁-adrenergic receptors. Furthermore, the combination of nebivolol and lenvatinib synergistically inhibited HCC proliferation both in vivo and in vitro. This study provides a rationale for repurposing nebivolol as a combination strategy for HCC therapy.