Purpose Gasdermin D (GSDMD) is a cytoplasmic protein that is encoded by the gasdermin family GSDMD gene and is the ultimate executor of pyroptosis. Pyroptosis is a mode of lysis and inflammation that regulates cell death, ultimately leading to cell swelling and rupture. In sepsis, a dysregulated host response to infection frequently results in hyperinflammatory responses and immunosuppression, eventually leading to multiple organ dysfunction. Pyroptosis regulates innate immune defenses and plays an important role in the process of inflammatory cell death, and the absence of any link in the entire pathway from GSDMD to pyroptosis causes bacterial clearance to be hampered. Under normal conditions, the process of pyroptosis occurs much faster than apoptosis, and the threat to the body is also much greater. Materials and methods We conducted a systematic review of relevant reviews and experimental articles using the keywords sepsis, Gasdermin D, and Pyroptosis in the PubMed, Scopus, Google Scholar, and Web of Science databases. Conclusion Combined with the pathogenesis of sepsis, it is not difficult to find that pyroptosis plays a key role in bacterial inflammation and sepsis. Therefore, GSDMD inhibitors may be used as targeted drugs to treat sepsis by reducing the occurrence of pyroptosis. This review mainly discusses the key role of GSDMD in sepsis.