Cyclosporine A(CsA), a classic immunosuppressant, is mainly applied for solid organ transplantation and some autoimmune diseases by suppressing T lymphocytes. Early studies showed that the application of CsA is primarily focused on chronic but not acute inflammation, nevertheless, increasing evidence supporting a role for CsA in acute inflammation, although most of proofs come from experimental models. It has long been known to us that the nuclear factor of activated T cells (NFAT) is the target of CsA to regulate T lymphocytes. However, NFAT also contributes to the regulation of innate immune cells, thus, CsA can not only target lymphocytes but also innate immune cells such as monocytes/macrophages, dendritic cells and neutrophils, which provides a basis for CsA to act on acute inflammation. Moreover, some other pathophysiological events in acute inflammation such as decreased vascular activity, mitochondrial dysfunction and endogenous cell apoptosis can also be alleviated by CsA. There being a moderate successes in the application of CsA for experimental acute inflammation such as sepsis, trauma/hemorrhagic shock and ischemic/reperfusion injury, yet data of the clinical treatment is not clear. In this review, we will critically analyze the existing hypotheses, summarize the application of CsA and its possible mechanisms in various acute inflammation over the past few decades, hope to provide some clues for the clinical treatment of acute inflammation.