Objective This study aims to examine the expression of nuclear factor κB (NF-κB)/B cell lymphoma-2 (Bcl-2) signal pathway and glycogen synthase kinase 3β (GSK-3β) in oral squamous cell carcinoma (OSCC) and provide references for the early diagnosis and prognosis evaluation of OSCC.Methods A total of 55 cases of OSCC and 10 cases of paracancerous mucosa were examined in this study. Their expressions of GSK-3β, NF-κB and Bcl-2 were detected using the SP method immunohistochemistry. The correlation between their expression in OSCC and the clinical and pathological peculiarity of OSCC was analyzed.Results The positive expression of GSK-3β, NF-κB, and Bcl-2 in OSCC were significantly higher than that in paracancerous mucosa (P0.05). The expression of Bcl-2 was significantly correlated with the degree of tumor differentiation (P0.05). Strong positive correlations were observed among the expressions of GSK-3β, NF-κB, and Bcl-2 (PConclusion The positive expression of GSK-3β, NF-κB, and Bcl-2 in OSCC are significantly higher than that in paracancerous mucosa. Detecting GSK-3β, NF-κB, and Bcl-2 in OSCC may have implications in the early diagnosis and prognosis evaluation of OSCC.