Sepsis is the body's response to infection, which can result in multiple organ failure. The immune imbalance in patients with sepsis leads to high mortality. Recent research has greatly advanced our understanding of sepsis pathophysiology, especially in the regulation of inflammatory pathways and immune suppression. S100A9, an alarmin, plays a critical role in modulating the immune response during sepsis and is associated with the potential for multiple organ dysfunction. In the early stage of sepsis, S100A9 can represent the occurrence of inflammation, while in the late stage of sepsis, S100A9 is related to immune suppression. This review summarizes the latest developments in S100A9 research, including its biological functions, role in immune responses, effects on organ damage across different systems during sepsis, and potential clinical applications. It provides insights into the interactions between S100A9 and the immune response and explores S100A9's involvement in sepsis-associated organ injuries. Additionally, this review outlines a framework for future applications of targeted S100A9 interventions and therapeutic strategies to reduce organ injury in sepsis.