Histamine receptor H3 (HRH3) is mainly expressed in the central nervous system, where it is involved in the regulation of the release of various neurotransmitters in the brain. Recent studies have demonstrated that the expression of HRH3 is upregulated in several types of cancer. However, the functional effect of HRH3 on tumor progression remains largely unknown, particularly in hepatocellular carcinoma (HCC). In the present study, the expression of HRH3 in 96 HCC patients was first evaluated, and its clinical significance was analyzed. Subsequently, the functional roles of HRH3 in HCC growth and metastasis were systematically explored in vitro and in vivo using its agonist (imetit) or antagonist (clobenpropit). It was observed that HRH3 was significantly upregulated in HCC tissues, while its expression was significantly associated with recurrence‑free survival and overall survival in HCC patients. Functional experiments also demonstrated that HRH3 upregulation facilitated the growth and metastasis of HCC cells by inducing the formation of lamellipodia. These findings revealed that HRH3 serves an important role in the growth and metastasis of HCC cells, which provides experimental evidence supporting the application of HRH3 as a potential therapeutic target in HCC treatment.