Inflammation is closely related to oral squamous cell carcinoma (OSCC). However, its mechanism is still obscure. Toll-like receptor 2 (TLR2) plays an important role in oral chronic inflammatory diseases, but the role of TLR2 in OSCC is unclear. Here, we investigated the expression of TLR2 expression in OSCCs and examined the potential role of TLR2 in OSCC through its association with clinicopathological features and patient outcome. We used 4-nitroquinoline 1-oxide (4-NQO) to induce a tongue cancer model in TLR2-/- and wild type (WT) mice. Histological and clinical results both indicated that TLR2 played a protective role in oral tumorigenesis. The results of a cytometric bead array (CBA) indicated that TLR2 deficiency resulted in Th1 and Th2 cytokine abnormalities, especially Th2 abnormalities. Immunohistochemistry also showed that TLR2 deficiency increases the number of tongue-infiltrating M2 macrophages. Overall, our results demonstrated that TLR2 plays an important role in the prevention of oral tumorigenesis and affects the levels of Th2 cytokines and tongue-infiltrating M2 macrophages; therefore, it may be used to prevent the development of oral cancer.