Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, associated with viral hepatitis, alcohol consumption, and non-alcoholic fatty liver disease. Hepatocyte nuclear factor 4 alpha (HNF4α), a crucial transcription factor for liver function (glucose and lipid metabolism, bile acid homeostasis, and cellular differentiation), is often dysregulated in HCC progression. This review provides a comprehensive overview of the role of HNF4α in hepatic oncogenesis, providing novel inshight into its regulatory effects on epithelial-mesenchymal transition (EMT), metabolic alterations (including the Warburg effect), cell cycle control, and tumor microenvironment. We also discuss therapeutic strategies targeting HNF4α focusing on restoring metabolic balance and inducing apoptosis. This integrated analysis advances our understanding of HNF4α's contribution to HCC and may pave the way for the development of targeted therapies (Fig. 1).