Age-related macular degeneration (AMD) is a complex multifactorial disease associated with the dysfunction of retinal pigment epithelium (RPE). Aloperine is a quinolizidine alkaloid that has been proven to possess broad pharmacological activities. However, the effects of aloperine on AMD remain unclear. In the present study, we used hydrogen peroxide (H(2)O(2)) to induce oxidative injury in human RPE cells (ARPE-19 cells). ARPE-19 cells were pretreated with different concentrations of aloperine for 2 h, followed by H(2)O(2) exposure. Cell cytotoxicity was determined using lactate dehydrogenase (LDH) release assay. Cell viability was measured using Cell Counting Kit-8 (CCK-8) assay. The reactive oxygen species (ROS) generation, malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-PX) activity were detected to reflect oxidative status. Western blot was performed to detect the expressions of bcl-2, bax, nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). The activity of caspase-3 was also assessed to indicate cell apoptosis. In addition, ARPE-19 cells were transfected with siNrf2 to knock down Nrf2. Our results showed that pretreatment with aloperine elevated the reduced cell viability of H(2)O(2)-induced ARPE-19 cells in a dose-dependent manner. Aloperine greatly decreased the production of ROS and MDA, and increased the activities of SOD and GSH-PX in H(2)O(2)-stimulated ARPE-19 cells. H(2)O(2)-caused a decrease in bcl-2 expression and increases in bax expression and caspase-3 activity were mitigated by aloperine. Moreover, aloperine treatment enhanced the expression levels of Nrf2 in nuclear fraction and the HO-1 expression in lysates. Knockdown of Nrf2 reversed the protective effects of aloperine on H(2)O(2)-induced ARPE-19 cells. In conclusion, these findings demonstrated that aloperine protected ARPE-19 cells from H(2)O(2)-induced oxidative stress and apoptosis in part via activating the Nrf2/HO-1 signaling pathway. The findings suggested a therapeutic potential of aloperine for the treatment of ADM.