Hepatitis B virus (HBV) X protein (HBx) plays a key role in the initiation and progression of HBV infection‑induced hepatocellular carcinoma (HCC). Oncogenic microRNA-21 (miR-21) can be modulated by HBx protein in HCC. However, critical regulator genes in the pathway of HBx-induced miR-21 in HCC remain unclear. This study aimed to investigate the role of HBx-induced miR-21 in the apoptosis of HCC cells. In the study, interleukin-12 (IL-12) was demonstrated as a direct target of miR-21 by dual‑luciferase report assay, and miR-21 was highly expressed in HCC cells (HepG2 and HepG2 2.2.15) compared to L02 cells, but IL-12 was weakly expressed as detected by real-time quantitative PCR (RT-qPCR). Furthermore, miR-21 mimics, inhibitor, HBx-targeted siRNA, and the HBx overexpression vector (pHBx) were used to observe the regulatory effects of HBx-induced miR-21 via IL-12, and cell apoptosis was assessed. The results showed that overexpression of HBx resulted in the inhibition of IL-12. A high level of miR-21 resulted in a significant increase in proliferation and a decrease in IL-12 expression. Inhibition of miR-21 resulted in a significant increase in apoptosis and increased IL-12 expression. The results suggest that HCC cell apoptosis was suppressed at least partially through HBx-induced miR-21 by targeting IL-12.