Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.