Introduction: Cigarette smoke (CS) is a major contributor to respiratory and systemic diseases, primarily due to its ability to induce cellular damage and chronic inflammation. While apoptosis has long been recognized as the dominant form of cell death resulting from CS exposure, recent findings highlight pyroptosis—a caspase-1 (CASP-1)-dependent, pro-inflammatory form of programmed cell death—as a key pathological mechanism. Pyroptosis is characterized by gasdermin D cleavage, pore formation in the cell membrane, and the release of inflammatory cytokines, particularly interleukin-1β and interleukin-18. Aims and Methods: This review synthesizes evidence from peer-reviewed articles published between 2014 and 2024, identified through searches in PubMed, Scopus, Web of Science, and Google Scholar. Search terms included “pyroptosis,” “cigarette smoke,” “inflammasome,” “caspase-1,” and “gasdermin D.” Only English-language articles from reputable, Scopus-indexed journals were included. Studies focusing on pyroptotic mechanisms, disease progression, and therapeutic interventions were prioritized. Results: Numerous studies demonstrate that CS activates inflammasomes, triggering CASP-1 activation and gasdermin D-mediated pyroptosis. This mechanism exacerbates chronic pulmonary diseases such as chronic obstructive pulmonary disease and emphysema and also plays a role in extrapulmonary conditions including atherosclerosis, liver dysfunction, and neuroinflammation. Inhibitors of CASP-1 and inflammasome components, as well as natural bioactive compounds, have shown potential in suppressing pyroptotic pathways and alleviating CS-induced tissue damage. Conclusions: Pyroptosis represents a critical inflammatory pathway in CS-induced diseases. Targeting inflammasome signaling and pyroptotic mediators offers a promising strategy for therapeutic development. A deeper understanding of this cell death mechanism could inform novel interventions to combat the widespread impact of smoking-related pathology. Implications: This review elucidates the critical role of pyroptosis as a key inflammatory mechanism in response to the toxic effects of cigarette exposure. By synthesizing recent scientific evidence, it underscores the involvement of pyroptotic pathways in the pathogenesis of tobacco-related diseases, highlighting their contribution to tissue damage and disease progression. A deeper understanding of these mechanisms may facilitate the identification of novel therapeutic targets aimed at mitigating the detrimental health effects of cigarette smoke. These insights could further inform the development of preventive and therapeutic strategies to alleviate the inflammatory burden associated with chronic cigarette exposure. © The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.