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Objective: To discover the expression pattern and potential underlying mechanism of the caspase recruitment domain‐containing protein 9 (CARD9) in oral squamous cell carcinoma (OSCC). Methods: Caspase recruitment domain‐containing protein 9 expression was detected by qRT‐PCR and Western blot in OSCC tissues and cells, and OSCC (CGHNC9 and OECM‐1) cell lines were divided into control, NC siRNA, and CARD9 siRNA groups. Then, MTT, flow cytometry, wound‐healing, and Transwell assays were carried out to determine the changes in cellular biological characteristics. Immunoblot assay was performed for the expressions of NF‐κB pathway. Finally, we constructed the xenograft models in nude mice to validate the in vivo effect of CARD9 siRNA on OSCC cell growth. Results: Caspase recruitment domain‐containing protein 9 was upregulated in both OSCC tissues and cells, exhibiting a close relation with major clinicopathological features of OSCC patients. Transfection of CARD9 siRNA inhibited the proliferation, migration, and invasion of OSCC cells with the enhanced cell apoptosis, and meanwhile, CARD9, p‐p65/p65, p‐IKKα/IKKα, and p‐IkBα/IkBα were downregulated. The tumor formation assay on nude mice also suggested that CARD9 siRNA might block the in vivo growth of OSCC cells. Conclusion: Caspase recruitment domain‐containing protein 9 suppression results in the upregulation of NF‐κB pathway with suppressed proliferation, migration, and invasion of OSCC cells and facilitates the apoptosis. [ABSTRACT FROM AUTHOR]