Sepsis is a life-threatening organ dysfunction caused by uncontrolled body reactions due to infection. Calprotectin (S100A8/A9), also known as myeloid-related protein MRP8/14, is an alarm element that plays a key role in the regulation of inflammation. In the process of occurrence and development of sepsis, it plays the role of anti-microorganism, regulating inflammation and immunity, as well as participating in intercellular signal transmission and anti-proliferation, thus has great potential to become a new diagnostic marker and therapeutic intervention target. In this paper, the distribution, structure, and biological functions of calprotectin S100A8/A9 are summarized, the mechanism of calprotectin S100A8/A9 in the occurrence and development of sepsis is discussed, and optimization and innovative application of research design in the future are prospected.