Objective To analyze the expression, protein-protein interaction network, and clinical significance of histamine receptor H3 (HRH3) in hepatocellular carcinoma (HCC) using a public database. Methods The ULACAN database was used to analyze the expression of HRH3 in HCC and normal liver tissues. The STRING database was used to study the protein-protein interaction network, GO, and KEGG pathway of HRH3. The Kaplan-Meier Plotter database was used to study the relationship between the expression of HRH3 and the prognosis of HCC. Results The expression of HRH3 was significantly higher in HCC than in normal liver tissues ( P< 0. 05). Moreover, the expression of HRH3 was not associated with sex, tumor stage, tumor differentiation, lymph node metastasis, or TP53 mutation in HCC. Furthermore, HRH3 interacted closely with 5-hydroxytryptamine receptor family members and metabotropic glutamate receptor family members, functioning as a G protein-coupled receptor to transmit signals in cells. High expression of HRH3 was associated with a good prognosis in the early stage of HCC and with a poor prognosis in the advanced stage of HCC. Conclusions The expression of HRH3 was increased in HCC. HRH3 functioned as a G protein-coupled receptor in HCC cells. HRH3 might function as a tumor suppressor gene in the early stage of HCC and as an oncogene in the advanced stage of HCC.