Objectives: Cyclo(His-Pro) (CHP) is an endogenous cyclic dipeptide that exerts cellular protective effects against anti-oxdative damages. However, the role and mechanisms for CHP in preventing cisplatin-induced nephrotoxicity remains largely unknown. In this study, we sought to investigate whether and how cyclo (His-Pro) prevents in cisplatin-induced acute kidney injury (AKI) mouse model.  Methods: In this study, a single intraperitoneal injection of cisplatin (10 mg/kg) was employed to induce AKI in ICR mice. To determine the role of CHP on cisplatin-induced AKI, the mice were pretreated with at dosage CHP (1 mg/kg) orally for 7 days before cisplatin injection. To explore the cell protective effect of CHP, in vitro study was also performed with primary cultured human proximal tubular cells (hTECs), hydrogen peroxide was administered to induce oxidative stress. Results: The mice developed severe acute kidney dysfunction exhibited as elevated BUN and creatinine level at day 2 after cisplatin injection. Mice with pretreatment of CHP showed markedly attenuated cisplatin-induced acute kidney injury. Additionally, pretreatment of CHP improved the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) which are the enzymes to defense against oxidative stresses. Comparable findings were observed in the protein expression of p-ERK, p-JNK, c-Fos, and c-Jun which is associated with inflammation and apoptosis. In primary cultured human tubular epithelial cells (hTECs) CHP showed a protective effect on oxidative stress induced by hydrogen peroxide. CHP effected on downregulation of inflammatory cytokines through inhibition of NF-kB signaling pathway. Conclusions: Together, this study demonstrated that CHP may protect against hydrogen peroxide-induced epithelial cell apoptosis and cisplatin-induced AKI through inhibiting MAPK and NF-κB signaling pathways.