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Objective: The aim was to research ACTL6A's role in oral squamous cell carcinoma (OSCC). Methods: OSCC and normal samples were obtained from patients and public databases. GSEA was performed. CIBERSORT was utilized to analyze immune landscape. Kaplan–Meier survival analysis and multivariate Cox regression analysis were conducted. After knocking down ACTL6A, we performed MTT assay, transwell assays, and flow cytometry to detect the impact of knockdown. Results: ACTL6A expressed higher in OSCC samples than normal samples. The CNV and mutation rate of TP53 was higher in ACTL6A high‐expression group. TFs E2F7 and TP63 and miRNA hsa‐mir‐381 were significantly related to ACTL6A. ACTL6A could influence immune microenvironment of OSCC. Knockdown of ACTL6A inhibited OSCC cells' proliferation, migration, and invasion. ACTL6A was able to predict OSCC prognosis independently. Conclusion: ACTL6A expressed higher in OSCC than normal samples and it could be used as an independent prognostic marker in OSCC patients. [ABSTRACT FROM AUTHOR]