BACKGROUND Diabetic retinopathy (DR) is a macrovascular complication that occurs in diabetic patients. Conventional treatments for the management of DR have many limitations. Thus, the present investigation evaluated the protective effect of fangchinoline against diabetic retinopathy (DR). MATERIAL AND METHODS DR was induced by streptozotocin (STZ; 60 mg/kg; i.p.) and rats were treated with fangchinoline 1, 3, and 10 mg/kg for 16 weeks. DR was confirmed by determining the concentration of advanced glycation end-products (AGEs) and morphology of retinal tissues. Parameters of oxidative stress and expression of inflammatory cytokines and receptor for advanced glycation end-products (RAGE) in the retinal tissue were determined by Western blot assay and reverse transcription polymerase chain reaction (RT-PCR). Moreover enzyme-linked immunosorbent assay (ELISA) was used to determine the apoptosis index and activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the retinal tissues. RESULTS Our study reveals that the concentration of glycosylated hemoglobin (HbA1c) and glucose in the plasma and AGEs in the retinal tissue were significantly reduced in the fangchinoline group compared to the DR group. Moreover, treatment with fangchinoline attenuated the altered retinal morphology and expression of inflammatory mediators and RAGE in the retinal tissues of DR rats. There was a significant (p<0.01) decrease in oxidative stress, activity of NF-κB, and apoptosis index in the fangchinoline group compared to the DR group of rats. CONCLUSIONS Our investigation shows that fangchinoline attenuates the apoptosis of retinal cells in STZ-induced diabetic retinopathy rats by inhibiting the RAGE/NF-κB pathway.