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In this study, the anti-tumor activity of ilimaquinone (IQ), a sesquiterpene quinone isolated from marine sponge <i>Halichondria</i> sp., in oral squamous cell carcinoma (OSCC) cells, was investigated. IQ suppressed the viability of the OSCC cell lines SCC4 and SCC2095 with IC₅₀ values of 7.5 and 8.5 μM, respectively. Flow cytometric analysis demonstrated that IQ induced caspase-dependent apoptosis in SCC4 cells and modulated the expression of several cell growth-related gene products, including Akt, p38, Mcl-1, and p53. Notably, p53 knockdown caused higher resistance to IQ’s anti-tumor activity. In addition, IQ increased reactive oxygen species generation, which was partially reversed by the addition of antioxidants. Furthermore, it triggered autophagy, as evidenced by acidic organelle formation and LC3B-II and Atg5 expression in SCC4 cells. Pretreatment with the autophagy inhibitor 3-methyladenine or chloroquine partially decreased IQ-induced apoptosis, suggesting that IQ induced protective autophagy. In summary, IQ has potential to be used in OSCC therapy.