<p>Long noncoding RNAs (lncRNAs) selectively incorporated into exosomes contribute to the tumorigenesis of various cancers. However, the role of the lncRNA FLG-AS1 in oral squamous cell carcinoma (OSCC) has yet to be investigated. Hence, the current study aimed to evaluate the potential role of exosome-derived FLG-AS1 in OSCC. The expression of FLG-AS1 and fat mass and obesity-associated protein (FTO) in OSCC samples were determined via real-time quantitative polymerase chain reaction (RT-qPCR). The role of FLG-AS1 in OSCC was investigated by performing CCK8, flow cytometry, and transwell assays. Additionally, bioinformatics, methylated (m6A) RNA immunoprecipitation, and RT-qPCR were performed to evaluate the n6-methyladenosine (m6A) modification of FLG-AS1 and its underlying mechanism. Characterization of exosomal FLG-AS1 in OSCC cells was achieved through transmission electron microscopy, nanoparticle tracking analysis, Western blot analysis of CD63 and CD9, and RT-qPCR. Finally, the effects of exosomal FLG-AS1 on OSCC cell malignancy was analyzed using the aforementioned cell-based assays. Overall, our findings showed that low FLG-AS1 expression in OSCC restricted the malignant properties of OSCC cells. Furthermore, FTO reduced FLG-AS1 expression by mediating its m6A demethylation in OSCC cells. Exosomal FLG-AS1 expression was upregulated in OSCC cells, suggesting that it was packaged in the OSCC cell-derived exosomes, whereas exosome-derived FLG-AS1 overexpression vector reduced the malignant potential of the target OSCC cells. In conclusion, exosomal FLG-AS1 functions as a tumor suppressor in OSCC, while FTO can impair FLG-AS1 expression through m6A demethylation.</p>