Abstract: Head and neck squamous cell carcinoma (HNSCC) progression is closely associated with chronic inflammation mediated by the NLRP3 inflammasome within the tumor microenvironment (TME). The NLRP3 inflammasome integrates pathogen-associated and stress-induced signals to dynamically regulate IL-1β/IL-18 secretion and pyroptosis. Through its action, NLRP3 inflammasome exhibits a functional duality, exerting tumor-suppressive effects by activating the Caspase-1/GSDMD pathway to induce tumor cell pyroptosis while also driving malignant progression through remodeling of immunosuppressive TMEs. This remodeling includes driving M2-type macrophage polarization and suppressing NETs-associated pyroptosis, thereby promoting cancer stem cell maintenance and contributing to chemotherapy resistance. Preclinical studies have confirmed that NLRP3-targeted strategies, including small-molecule inhibitors (MCC950 and BAY11-7082), Bacopa monnieri , and IL-1 signaling biologics, significantly suppress tumor growth and metastasis in HNSCC and other cancers. In this review, we systematically decipher the NLRP3 regulatory network, evaluate the translational potential of targeted interventions, and offer novel therapeutic avenues to overcome treatment barriers in HNSCC.