Hepatoma is the sixth most malignant tumor in the world and the second leading cause of cancer death. Among the types of hepatoma, hepatocellular carcinoma (HCC) is the most important pathological type. For patients with early-stage HCC, the curative treatment is tumor resection. However, early diagnosis and treatment of HCC are difficult; the disease progresses rapidly, and the prognosis is poor. Due to the current limited treatment options for advanced HCC, the identification of new targeted agents is critical for the development of novel approaches to HCC treatment. Histone deacetylases (HDACs) is a protease that removes acetyl groups from histone lysine residues in proteins, and it plays an important role in the structural modification of chromosomes and the regulation of gene expression. Abnormally expressed HDACs can promote tumorigenesis by inducing biological processes such as cell proliferation, migration, and apoptosis inhibition. Since HDACs activity is upregulated in HCC, treatment regimens specifically inhibiting various HDACs have shown good efficacy. This article reviews the application of HDAC inhibitors in the treatment of HCC and explains their mechanisms of action. KEY MESSAGES: HDAC network and cellular effects of HDAC inhibitors. Role and mechanism of HDAC inhibitors in HCC. HDAC inhibitor combined with other ways to treat HCC. The side effects of HDACis in the treatment of HCC.