The role of epigenetic inactivation of secreted frizzled‑related protein 2 (SFRP2) and its functions in the development of oral squamous cell carcinoma (OSCC) remain to be elucidated. The present study demonstrated that SFRP2 mRNA was detected in 97.96% of tumor‑adjacent normal tissues, while its expression was only detected in 16.33% of the tumor samples. In addition, the loss of SFRP2 expression was associated with hypermethylation of its promoter. As expected, the overexpression of SFRP2 in OSCC cell lines (Tca8113) suppressed cell proliferation and arrested the cell cycle in the G1 phase. Overexpression of SFRP2 also effectively repressed tumor growth in xenograft animals. Mechanistic investigations revealed that SFRP2 inhibited the development of OSCC in vitro and in vivo through an increase in the expression levels of glycogen synthase kinase‑3β and a decrease in the expression level of cyclin D1, a direct read‑out gene of active Wnt signaling. In addition, an increase in the expression of β‑catenin was observed in the Tca8113/SFRP2 cells and in the animal models overexpressing SFRP2. Therefore, the results of the present study provide insight into the role of SFRP2 as a functional tumor suppressor in the development of OSCC through inhibition of the Wnt signaling pathway. Further studies on the precise mechanisms underlying the inhibition of Wnt signaling by SFRP2 and its association with β‑catenin are required.