In this study, we aimed to explore the effects of downregulated microRNA 21 (miR-21) on the expression of RECK and the proliferation and metastasis of oral squamous cell carcinoma (OSCC) cells. Sixty-five tumor tissues (TTs) and corresponding paracancerous tissue (PT) specimens were excised from patients with OSCC. The mRNA levels of miR-21 and RECK were determined in TTs and PTs using qPCR. To assess the effects of miR-21-mediated modulation of RECK expression on tumor behavior, the OSCC cell line CAL-27 was transfected with miR-21 mimic, miR-21 inhibitor, or negative control (miR-NC). Compared with PTs, TTs showed increased miR-21 level and decreased RECK mRNA and protein levels. Transfection of CAL-27 cells with miR-21 inhibitor upregulated RECK mRNA and protein expression, and transfection with miR-21 mimic downregulated RECK expression compared with that following transfection with miR-NC. After 48–72 h of transfection, the mir-21 mimic group exhibited higher cell proliferation rate than other groups. miR-21 is upregulated and RECK expression is downregulated in OSCC. Downregulation of miR-21 upregulates RECK via disinhibition, which in turn suppresses the proliferation and migration and accelerates the apoptosis of OSCC cells. Downregulation of miR-21 may be an effective strategy against OSCC.