Cisplatin (CP) is used as a chemotherapeutic drug for the treatment of various kinds of cancer. However, it is becoming increasingly difficult to ignore its side effects, especially nephrotoxicity which has to do with oxidative stress and inflammation. Procyanidin (PRO) has been proved to be a powerful antioxidant. Therefore, we investigated whether PRO could prevent Cisplatin-induced nephrotoxicity and explored the underlying mechanism. In cellular experiment, reactive oxygen species (ROS), the malondialdehyde (MDA) levels, the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) were measured for the assessment of cisplatin-induced oxidative cell damage. CCK-8 reagent and flow cytometry were used to detect the cell viability and apoptosis. Furthermore, the level of oxidative-related protein Nrf2 and HO-1 were carried out by western blot analysis. We found that cisplatin gave rise to the elevated levels of ROS and MDA and the decrease of the activities of T-SOD and GSH-PX with a related lower viability and higher apoptosis in HK-2 cells. Inversely, the pretreatment of PRO mitigated the oxidative damage, promoted the cell viability and lowered the apoptosis, activated nuclear related factor 2 (Nrf2) and elevated the expression of heme oxygenase-1 (HO-1), the above cytoprotection of PRO was blocked by siNrf2 or siHO-1. These results demonstrated that PRO has the potential to prevent cisplatin-induced nephrotoxicity through activation of Nrf2/HO-1 signaling pathway.