The secretory leukocyte protease inhibitor (SLPI) is mainly produced by immune cells and various epithelial cells, and is regulated by a variety of cytokines, such as transforming growth factor β1, interleukin 1β and tumor necrosis factor α. In addition to commonly known anti-protease activity, it has been found in recent years that SLPI plays essential roles in anti-apoptosis, regulating cell cycle, cell differentiation and proliferation, and inhibiting inflammatory response. SLPI can also assist the immune system to clear pathogens/damaged cells by enhancing the phagocytic function of phagocytes, so as to ameliorate tissue damage and promote repair. Moreover, recent studies have shown that the change of SLPI level in the serum of patients post cardiovascular surgery has a high diagnostic value in predicting the occurrence of acute kidney injury, suggesting that SLPI is involved in ischemia-reperfusion (IR) induced acute kidney injury. In this review, we summarized the expression, regulation, signaling pathways and associated biological events of SLPI in different organ injury models, and also discussed and evaluated the potential role of SLPI in renoprotection against IR induced acute kidney injury and its potential as a new biomarker.