Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus and is considered as a leading cause of blindness. Oxidative stress and inflammation are significant drivers for the development of DR. Eriodictyol, a flavonoid compound, was proved to possess anti‐inflammatory, antioxidative, and antidiabetic activities. However, the role of eriodictyol in DR has not been unveiled. In the current study, we explored the protective effects of eriodictyol on high glucose (HG)‐induced rat retinal ganglial cells (RGCs). The results suggested that eriodictyol improved cell viability of HG‐induced rat RGC‐5 cells in a dose‐dependent manner. Eriodictyol reduced the reactive oxygen species production and increased the activities of superoxide dismutase, glutathione peroxidase and catalase in rat RGC‐5 cells in response to HG stimulation. The production of proinflammatory cytokines including tumor necrosis factor alpha and interleukin‐8 was diminished after eriodictyol treatment. Eriodictyol also suppressed cell apoptosis induced HG in rat RGC‐5 cells. Furthermore, eriodictyol enhanced the nuclear translocation of nuclear factor erythroid‐2 (E2)‐related factor 2 (Nrf2) and elevated the expression of antioxidant enzyme heme‐oxygenase‐1 (HO‐1). These findings suggested that eriodictyol protects the RGC‐5 cells from HG‐induced oxidative stress, inflammation, and cell apoptosis through regulating the activation of Nrf2/HO‐1 pathway.