Numerous microRNAs (miRNAs) are dysregulated in tongue squamous cell carcinoma (TSCC), and their dysregulation has been demonstrated to have a strong correlation with TSCC progression via regulation of their targets. Therefore, miRNAs have potential use in the diagnosis and treatment of patients with TSCC. In the present study, miRNA‑758 (miR‑758) expression in TSCC tissues and cell lines was detected through reverse transcription‑quantitative polymerase chain reaction, and the effects of miR‑758 on TSCC cell proliferation and invasion were investigated by using Cell Counting kit‑8 and Transwell invasion assays. A luciferase reporter assay was performed to determine the target interaction between miR‑758 and metadherin (MTDH) in TSCC cells. The results revealed that miR‑758 was downregulated in TSCC tissues and cell lines. miR‑758 overexpression restricted the proliferation and invasion of TSCC cells. Additionally, MTDH was verified as a direct target gene of miR‑758 in TSCC cells. Furthermore, MTDH was observed to be upregulated in TSCC tissues, and the upregulation of MTDH was inversely correlated with miR‑758 expression. Moreover, restored MTDH expression significantly counteracted the suppressive effects of miR‑758 overexpression on TSCC cells. These results suggested that miR‑758 may prevent TSCC progression and development by directly targeting MTDH, thereby providing evidence that miR‑758 is a novel therapeutic target for the treatment of patients with TSCC.