Chemoresistance is a challenge for clinician in management of tongue cancer. Therefore, it is necessary to explore alternative therapeutic methods to overcome drug resistance. miRNAs are endogenous −22nt RNAs that play important regulatory roles by targeting mRNAs. miR-21, an essential oncogenic molecule, is associated with chemosensitivity of several human cancer cells to anticancer agents. In this study, we investigated the effects and molecular mechanisms of miR-21 in chemosensitivity of tongue squamous cell carcinoma cells (TSCC) to cisplatin. miR-21 expression was detected in tongue cancer tissue using RT-PCR and PDCD4 protein expression was measured using immunohistochemistry. miR-21 and(or) PDCD4 depleted cell lines were generated using miR-21 inhibitor and(or) siRNA. The viabilities of treated cells were analyzed using MTT assay. RT-PCR was used to detect miR-21 expression and immunoblotting was used to detect protein levels. Cell cycle and apoptosis were analyzed using propidium iodide (PI) staining and Annexin V/PI staining, respectively. The expression of miR-21 in tumorous tissue was significantly higher compared with adjacent normal tissue and loss of PDCD4 expression was observed in TSCCs. Transfection of miR-21 inhibitor induced sensitivity of TSCC cells (Tca8113 and CAL-27) to cisplatin. TSCC cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-21 inhibitor using Western blot analysis. In addition, the enhanced growth-inhibitory effect by miR-21 inhibitor was weakened after the addition of PDCD4 siRNA. Suppression of miR-21 or PDCD4 could significantly promote or reduce cisplatin-induced apoptosis, respectively. Our data suggest that miR-21 could modulate chemosensitivity of TSCC cells to cisplatin by targeting PDCD4, and miR-21 may serve as a potential target for TSCC therapy.