Hepatitis B virus (HBV) X protein (HBx) is a key regulatory protein that is involved in HBV infection, replication and carcinogenesis of hepatocellular carcinoma (HCC). The aim of the present study was to investigate the role of HBx in the progression and metastasis of liver cancer cells and to determine the underlying molecular mechanism of HBx in metastatic liver cancer cells. HBx protein expression was detected by western blot analysis, and microRNA (miR)‑21 levels were determined by reverse transcription‑quantitative polymerase chain reaction in the highly metastatic MHCC‑97H low metastatic MHCC‑97L and SMMC‑7721 liver cancer cell lines. The results demonstrated that the levels of HBx and miR‑21 were significantly increased in MHCC‑97H cells compared with MHCC‑97L and SMMC‑7721 cells. In addition, three pairs of small interfering (si)RNA specific to HBx were designed and synthesized to interfere with endogenous HBx in liver cancer cells, and the results demonstrated that knockdown HBx was associated with a corresponding decrease in miR‑21 expression. The MTT assay results demonstrated that cell viability significantly decreased in HBx‑siRNA cells compared with scramble siRNA‑transfected cells. In addition, transfection with an miR‑21 inhibitor inhibited MHCC‑97H cell proliferation. Furthermore, Transwell assay results revealed that downregulation of HBx and treatment with miR‑21 inhibitors contributed to the inhibition of MHCC‑97H cell invasion and metastasis. Western blot analysis demonstrated that miR‑21 inhibitors and HBx‑siRNA treatment led to the upregulation of phosphatase and tensin homolog (PTEN), and decreased levels of phosphoinositide 3‑kinase (PI3K), phosphorylated protein kinase B (Akt) and matrix metalloproteinase (MMP)‑2. The results of the present study indicated that HBx was positively associated with miR‑21 expression, and downregulation of miR‑21 and HBx suppressed MMP‑2 activity via the PTEN/PI3K/Akt signaling pathway. Therefore, HBx and miR‑21 may represent novel therapeutic targets for the treatment of HCC.