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Limited treatment options are available for hepatocellular carcinoma (HCC), especially in the advanced stage, which is associated with a poor prognosis. Many studies have demonstrated that hepatocyte nuclear factor 4α (HNF 4α) plays an important role in hepatic differentiation and the carcinogenesis of HCC. HNF 4α critically regulates hepatic differentiation by controlling a large number of genes involved in hepatic functions including metabolism, xenobiotic detoxification, bile acid synthesis, and serum protein production. It has also been confirmed to play an important role in the inflammatory environment in HCC. Thus, HNF 4α is considered to be a promising target for the treatment of HCC. Some studies have demonstrated that regulating HNF 4α expression in HCC had beneficial effects in in vivo and in vitro experiments. We herein review the role of HNF 4α in regulating hepatic metabolism and the inflammatory response, aiming to provide some ideas on induced hepatic differentiation therapy and regulating the inflammatory microenvironment for the treatment of advanced HCC.