MicroRNAs, a class of endogenous noncoding RNAs, regulate gene expression at the posttranscriptional level and thus take part in multiple biological processes. An increasing number of miRNAs have been found to be dysregulated in hepatocellular carcinoma (HCC) and are involved in liver tumorigenesis. In this study, miR-125a-5p was found to be obviously downregulated much more in hepatitis B virus (HBV)-related HCC. To investigate the effects of miR-125a-5p, miR-125a-5p was overexpressed in HepG2.2.15 and HepG3X cells. The findings have indicated that overexpression of miR-125a-5p dramatically inhibited cell proliferation and induced cell apoptosis. Furthermore, overexpression of miR-125a-5p could significantly decrease the secretion of HBsAg and HBeAg. In concordance to this, the expression of ErbB3 was upregulated in human HBV-related HCC tissue, HepG2.2.15 cells, and HepG3X cells. miR-125a-5p directly targeted ErbB3 and reduced both mRNA and protein levels of ErbB3, which promoted cell proliferation and suppressed cell apoptosis in HCC cells. Our results provide new insights into the function of miR-125a-5p in HBV-related HCC. It is beneficial to gain insight into the mechanism of HBV infection and pathophysiology of HBV-related HCC.