Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal failure. Modulation of oxidative stress is an effective therapeutic strategy for I/R injury. Perillyl alcohol (POH), a dietary monoterpene with antioxidant activity is found in a variety of plants. The study was carried out to investigate whether treatment of POH could reduce hypoxia/reoxygenation (H/R)-induced injury. H/R induced significant injury in HK-2 cells. H/R caused an increase in ROS level, apoptosis and ER stress. Meanwhile H/R also inhibited the cell viability and PI3K/Akt/eNOS signaling pathway. Pretreatment with POH prior to H/R improved cell viability, reduce ROS level, ER stress and apoptosis. Moreover, POH could also activate the PI3K/Akt/eNOS pathway. Therefore, POH may possess protective effects in H/R-induced cellular damage.