Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, with a high mortality rate. Genetic and epigenetic abnormalities are often observed in HCC, and epigenetic changes such as DNA methylation, histone alterations, chromatin remodeling, and non-coding RNA expression play an important role in the development and metastasis of HCC. This article aims to summarize the epigenetic changes involved in the progression of HCC, highlight the epigenetic modifications associated with HCC treatment, and outline the development progress of HCC epigenetic biomarkers and therapeutic targets for a deeper understanding of the epigenetics of HCC, especially the potential value of the combination of immunotherapy in HCC, in order to provide new ideas for clinical physicians to develop rational clinical strategies, improve overall patient survival, and predict treatment outcomes.