Redox mediated cancer therapeutics are of immense interest in the recent decade due to their anticancer activity. Piperine is the principal alkaloid of black and long pepper. Although its anticancer activity has been reported in number of cancers , the precise molecular mechanism of action remains to be unravelled. Hence, in this study, for the first time, we delineated the mechanistic insight into the effect of piperine against hepatocellular carcinoma (HCC).MTT analysis determined the dose and time dependent cytotoxicity of piperine against Hep G2 cells. Further molecular studies evidenced the prooxidant property of piperine by inducing H2O2 driven mitochondria-mediated apoptosis in Hep G2 cells by inhibiting the peroxide detoxifying enzyme Catalase. Molecular docking and western blotting analysis uncovered the piperine mediated receptor tyrosine kinase inhibition and mitigation of HCC progression. In addition, histological investigations of piperine - treated, DEN-induced HCC rats showed significant prognosis with apoptotic cell death. Whereas,co-treatment of an antioxidant EUK-134 significantly abrogated its chemotherapeutic activity substantiating its radical-mediated anticancer property. Altogether, this study shows that the piperine may be a promising prooxidant drug for the amelioration of hepatocellular carcinoma.