Sepsis is defined as a life-threatening condition caused by a dysregulated host response to infection, leading to multi-organ dysfunction, and representing a significant global health burden. The progression of sepsis is closely linked to disruptions in lung microbiota, including bacterial translocation, impaired barrier function, and local microenvironmental disturbances. Conversely, the worsening of sepsis exacerbates lung microbiota imbalances, contributing to multi-organ dysfunction. Recent culture-independent microbiological techniques have unveiled the complexity of the respiratory tract microbiome, necessitating a reassessment of the interactions between the host, microbes, and pathogenesis in sepsis. This review synthesizes current insights into the causes of microbiota dysbiosis and the regulatory mechanisms of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, as well as their interactions during sepsis and sepsis-induced organ dysfunction. In addition, we summarize novel diagnostic and therapeutic approaches from the current study that may offer promising prospects for the management of sepsis.