Background Long non‐coding RNAs (lncRNAs) have been extensively studied to participate in the carcinogenesis of various tumors. LncRNA FGD5‐AS1 has been studied as an oncogene in several cancers; however, the role it plays in oral squamous cell carcinoma (OSCC) still remains unclear. Methods Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to assess relevant RNAs expression. CCK‐8 and colony formation were combined to investigate cell proliferation. Flow cytometry was implemented to test the apoptosis of cell. Wound healing assay and transwell assays were conducted to investigate cell migration and invasion. Western blot assay was conducted to measure relevant protein expression. Results FGD5‐AS1 expression was aberrantly up‐regulated in OSCC tissue and cells. FDG5‐AS1 up‐regulation induced USP21 overexpression advances OSCC development. Knockdown of FGD5‐AS1 inhibited cell growth, migration, and invasion, yet promoted apoptosis. Conclusion FGD5‐AS1 regulates OSCC via competitively binding to miR‐520b against USP21. It could become a potential diagnostic biomarker for OSCC.