Objective: To explore the inhibitory effect of celecoxib (CELE) on the proliferation of tongue squamous cell carcinoma Cal-27 cells and its mechanism. Methods: A CCK-8 assay was used to investigate the cytotoxicity of different concentrations CELE(10, 20, 40, 60, 80, and 100 mol/L) at 24 and 48 h in Cal-27 cells. According to the concentration of CELE, samples were divided into a control group (0 μmol/L) and experimental groups (10, 20, and 40 μmol/L), and cell invasiveness was detected by the Transwell method. The expression levels of c-Myc and Cyclin D1 mRNA were detected with qPCR, and western blots were used to detect the expression of phosphate and tension homologue deleted on chromosome ten (PTEN), phospho-protein kinase B (p-AKT) (Thr308), c-Myc, cyclin D1 and other proteins in Cal-27 cells after 24 h of treatment with different doses of CELE (10, 20, and 40 μ mol/L) and after 6, 12, and 24 h of treatment with 40 μmol/L CELE. Results : The different concentrations of CELE were able to inhibit the proliferation of Cal-27 cells, and the higher the concentration of CELE was, the more significant the inhibition of the proliferation of Cal-27 cells was. The cell survival rates of cells exposed to 40 μmol/L CELE were 80% and 75% after 24 and 48 h, respectively. In the four groups of patients, the number of invasive cells was compared, and the results in decreasing order were the control group, 10 μmol/L CELE, 20 μmol/L CELE, and 40 μmol/L CELE. The expression level of c-Myc, cyclin D1 mRNA and the protein in P-AKT (Thr308), c-Myc, and cyclin D1 significantly decreased and the expression of PTEN protein increased in the Cal-27 cells after administration of CELE at different concentrations. Conclusion CELE can inhibit the proliferation of Cal-27 cells, possibly through inhibition of the expression of proliferation signal factors, such as c-Myc and cyclin D1, by activating the PTEN signaling pathway.