MicroRNA-126 (miR-126), an endothelial-specific miRNA located within intron 7 of epidermal growth factor‑like domain 7 (EGFL7), has been demonstrated to act as a tumor suppressor in various types of human cancer. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, we revealed that the expression of miR-126 was significantly decreased in OSCC tissues, when compared with that in their matched adjacent tissues, and its expression level was also reduced in Tca8113, OSCC-15 and CAL27 cell lines compared with normal tissues. The protein expression of EGFL7 was upregulated in OSCC tissues compared with their matched adjacent tissues as well as normal tissues, and Tca8113, OSCC-15 and CAL27 cells additionally demonstrated a positive expression of EGFL7. The overexpression of miR-126 significantly reduced the protein expression of EGFL7 in OSCC-15 cells, while transfection with the miR-126 inhibitor upregulated the EGFL7 protein level in OSCC-15 cells. Furthermore, transfection with an miR-126 mimic into OSCC-15 cells markedly suppressed cell proliferation, cell cycle progression, cell invasion and colony formation, while inducing cell apoptosis, which contrasted with the effects of transfection with an miR-126 inhibitor. The overexpression of miR-126 suppressed the secretion of two key regulators of angiogenesis, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which was also reversed by miR-126 inhibitor transfection. In conclusion, the present study demonstrated that miR-126 acts as a tumor suppressor in OSCC cells, partially at least via the downregulation of EGFL7. Thus, miR-126 may serve as a promising candidate for the treatment of OSCC.