Backgroud: Wogonin, an active flavonoid extracted from Scutellaria baicalensis Georgi, has many active activities, including anti-oxidant, anti-thrombotic and anti-tumor. However, its potential anti-proliferative and anti-metastatic properties in oral squamous cell carcinoma and the underlying mechanisms are still unclear. In the present study, we assessed the effect of wogonin on oral squamous cell carcinoma and detected its potential molecular mechanisms. Methods: The CCK-8 and EdU assays were performed to test cell viability and cell proliferation. In addition, flow cytometry was conducted to detect cell apoptosis and the expressions of apoptosis-related proteins were evaluated by western blotting. Further, cells migration and invasion were evaluated by the wound healing assay and Transwell invasion assay, respectively. Results: The result indicated that wogonin significantly suppressed cells viability and proliferation of oral squamous cell carcinoma cells Cal-27 and SCC4 in a concentration-dependent manner. In addition, wogonin could induce apoptosis of Cal-27 and SCC4 cells through promoting the expressions of Bax, Caspase-3 and Caspase-9 and down-regulating the expression of Bcl-2. Moreover, wogonin notably decreased Cal-27 and SCC4 cells migration and invasion, which may be associated with down-regulation of extracellular matrix degradation-associated proteins. Further, the levels of beta-catenin and its target genes, including c-myc and cyclinD1 were significantly decreased in the wogonin-treated Cal-27 and SCC4 cells, which indicated that wogonin could block the Wnt/beta-catenin signaling pathway. Notably, inhibition of the Wnt/beta-catenin signaling pathway could suppress Cal-27 and SCC4 cells viability, decrease cells proliferation, induce cells apoptosis, and restrain cells migration and invasion. Conclusions: Taken together, our findings suggested that wogonin was a potent remedy applied to oral squamous cell carcinoma treatment in the future.