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Lysine demethylase 5C (KDM5C) is a member of the KDM family of demethylases and has been reported as a cancer driver. This study aimed to probe the function of KDM5C in the development of liver hepatocellular carcinoma (LIHC) and the molecules of action. According to data from publicly accessible bioinformatic databases, KDM5C is highly expressed in LIHC and associated with poor patient prognosis. High expression of KDM5C was detected in acquired LIHC cell lines. Downregulation of KDM5C weakened proliferation, migration, invasiveness, and resistance to death of the LIHC cells in vitro, and it reduced growth of the xenograft tumors in nude mice. Inter‐alpha‐trypsin inhibitor heavy chain 1 (ITIH1) was predicted as a downstream gene negatively regulated by KDM5C. KDM5C‐regulated H3K4me1 modification at the promoter region of ITIH1, inducing its transcriptional inactivation. Further downregulation of ITIH1 in cancer cells blocked the functions of KDM5C silencing and restored the malignant behaviors of LIHC cells. The activity of the PI3K/AKT signaling was decreased following KDM5C downregulation but recovered upon ITIH1 silencing. In conclusion, this study suggested that KDM5C epigenetically reduces ITIH1 and activates the PI3K/AKT signaling pathway to promote LIHC progression. [ABSTRACT FROM AUTHOR]