OBJECTIVE: Thymoquinone (TQ), the active constituent of Nigella sativa, has been shown to have anticancer effects in head and neck squamous cell carcinoma (HNSCC). This review aims to outline the properties of TQ, the known drivers in HNSCC formation, and summarize the anticancer effects of TQ in SCC. DATA SOURCES: Three databases (PubMed, Embase, and Google Scholar) were queried for the key words thymoquinone squamous cell carcinoma. REVIEW METHODS: Publications that were not original research and publications that did not have full-text available for review were excluded. RESULTS: Sixteen research articles met the inclusion criteria. Our review demonstrates that TQ-induced cytotoxicity is associated with increased expression and activity of the tumor suppressor p53, proapoptotic proteins Bax and caspases, as well as decreased expression and activity of antiapoptotic proteins Bcl-2 and Mdm2. Additionally, TQ modulates cell-survival pathways such as the PI3k/Akt pathway. TQ synergizes with therapeutics including cisplatin and radiation. Early TQ administration may prevent carcinogenesis via upregulation of antioxidant enzymes, and TQ administration in the presence of cancer can result in disease mitigation via induction of oxidative stress. CONCLUSION: TQ acts as an upregulator of proapoptotic pathways and downregulator of antiapoptotic pathways, modulates the oxidative stress balance in tumor development, and works synergistically alongside other chemotherapeutics to increase cytotoxicity. TQ has the potential to prevent carcinogenesis in patients who are at high-risk for SCC and adjuvant treatment for SCC patients undergoing conventional treatments. Future studies should aim to identify specific populations in which TQs effects would be the most beneficial. LEVEL OF EVIDENCE: Not available.