The regulation mechanism and significance of microRNA-122 (miRNA-122) expression are unclear. The aim of this study was to investigate the effects of DNA methylation on liver-specific miRNA-122 expression, cell proliferation, and apoptosis in hepatocellular carcinoma. Methylation of the miRNA-122 promoter region was detected through methylation sequencing. The level of miRNA-122 expression was measured using real-time quantitative polymerase chain reaction. The proliferation and apoptosis of hepatocellular cell lines were detected using flow cytometry and Cell Counting Kit-8 assays.