Hepatocellular carcinoma (HCC) remains a significant global health concern with limited treatment options. Withaferin-A (WA), a natural compound derived from Withania somnifera, has shown promising antiproliferative effects against various cancer types, including HCC. However, its efficacy as a standalone treatment for HCC is limited. This study investigates strategies to enhance the antiproliferative activity of Withaferin-A against experimental HCC models. Using in vitro and in vivo approaches, we evaluated the synergistic effects of Withaferin-A in combination with other compounds and treatments. Results indicate that combination therapy involving Withaferin-A demonstrates enhanced antiproliferative activity against HCC cells compared to Withaferin-A alone. Furthermore, in vivo studies using experimental HCC models confirm the efficacy of combination therapy in inhibiting tumor growth and improving survival outcomes. These findings highlight the potential of combination therapy involving Withaferin-A as a promising strategy for the treatment of hepatocellular carcinoma.