Numerous microRNAs (miRNAs) have been demonstrated to be downregulated or upregulated in hepatocellular carcinoma (HCC) and play important roles in its occurrence and development. Therefore, the investigation of miRNAs and their functions implicated in the genesis and development of HCC may provide key clues for the identification of effective therapeutic approaches for patients with this disease. The aims of the present study were to detect miRNA‑466 (miR‑466) expression in HCC tissues and cell lines and to determine its effects on HCC cell proliferation, apoptosis and metastasis, as well as to explore the mechanisms underlying the tumor‑suppressing roles of miR‑466 in HCC. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to detect miR‑466 expression in HCC tissues and cell lines. The effects of miR‑466 upregulation on HCC cell proliferation, apoptosis, migration and invasion were determined using Cell Counting Kit‑8 assay, flow cytometry analysis and Transwell chamber assay, respectively. The potential target gene of miR‑466 was predicted using bioinformatic analysis, which was further confirmed by luciferase reporter assay, RT‑qPCR and western blot analysis. It was found that miR‑466 was obviously decreased in HCC tissues and cell lines. The results of functional experiments revealed that restoration of miR‑466 expression suppressed the proliferation, induced apoptosis, and reduced the metastasis of HCC cells. In addition, metadherin (MTDH) was identified as a direct target of miR‑466 in HCC cells. Furthermore, MTDH was upregulated in HCC tissues, which was inversely correlated with the miR‑466 level. Moreover, inhibition of MTDH displayed similar tumor‑suppressing roles as miR‑466 upregulation in HCC cells. In addition, MTDH reintroduction restored the tumor‑suppressor activity of miR‑466 overexpression in HCC cells. These findings suggest that miR‑466 is a potential therapeutic tool for HCC therapy.