Objective This study aims to detect the expression level of interleukin-23 (IL-23) in tongue squamous cell carcinoma tissues and its relationship with clinical prognosis, as well as explore the anti-apoptotic and drug resistance of the tongue squamous cell line-SCC9 before and after treatment with IL-23.Methods The expression of IL-23 in tumor tissues from 28 tongue cancer patients was analyzed by immunohistochemistry assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Wingless-related integration site (Wnt)1 and c-myc in SCC9 cells treated with different IL-23 concentrations. After interferencing the β-catenin with small interfering RNA (siRNA), the expression of β-catenin, B-cell lymphoma-2 (Bcl-2), ATP-binding cassette sub-family G member 2 (ABCG2), and permeabilityglycoprotein (P-gp) in SCC9 was measured by Western blot analysis. The effect of IL-23 on the apoptotic resistance of SCC9 to cisplatin was examined by methyl thiazolyl tetrazolium test.Results The expression of IL-23 in tongue cancer tissues was correlated with lymphatic metastasis, nerve invasion, and the recurrence after therapy (PPConclusion IL-23 activates the Wnt pathway in tongue squamous cell carcinoma, thereby enhancing its resistance to apoptosis and drug.