Diabetic retinopathy (DR) is a common complication of diabetes mellitus and results in acquired blindness among working-age adults. It has been demonstrated that high glucose (HG)-induced oxidative stress and cell apoptosis in retinal pigment epithelial (RPE) cells are major factors for the pathogenesis of DR. Sauchinone, one of the active lignan isolated from Saururus chinensis, was reported to possess anti-oxidant and anti-apoptosis effects. In the present study, we investigated the effects of sauchinone on HG-induced oxidative stress and apoptosis in ARPE-19 cells. Our results proved that sauchinone improved the cell viability of HG-induced ARPE-19 cells. Moreover, sauchinone treatment caused a decrease in intracellular reactive oxygen species (ROS) generation and an increase in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). Besides, flow cytometry showed that the apoptotic rate in sauchinone-treated ARPE-19 cells obviously decreased as compared in the HG-treated cells. Western blot indicated that sauchinone treatment caused a significant decrease in bax expression and increase in bcl-2 expression in HG-treated ARPE-19 cells. Sauchinone treatment enhanced the HG-caused induction of p-Akt, nuclear factor erythroid 2-related factor (Nrf2), and heme oxygenase-1 (HO-1) expressions in ARPE-19 cells. However, the inhibitor of Akt, LY294002, reversed the effects of sauchinone on cell viability, oxidative stress, and cell apoptosis in HG-treated ARPE-19 cells. These findings suggested that sauchinone treatment prevented HG-induced oxidative stress and apoptosis via regulating the Akt/Nrf2/HO-1 pathway in HG-induced RPE cells. These findings suggested that sauchinone might be a therapeutic agent for the treatment and prevention of DR.