The present study was designed to evaluate the effects of Atorvastatin (ATO) plus melatonin (MEL) on streptozocin-induced diabetic retinopathy (DR) in rats. Diabetes was induced in Wistar rats with an intraperitoneal injection of streptozocin (50 mg/kg). Animals were randomly assigned to one of the following groups (8 rats/group): Control group, Diabetic group, Diabetic + MEL group (20 mg/kg/day), Diabetic + ATO group (10 mg/kg/day), Diabetic + MEL + ATO group (as above). Treatments were started one week after induction of diabetes and continued for 7 weeks. At the end of the experiment, angiography was performed and rats were killed and retinas were harvested for pathological and molecular examinations. Administration of MEL reduced the ﬂuorescein leakage, and MDA and ROS levels compared to diabetic group. Treatment with ATO only reduced ROS levels compared to diabetic group, while administration of ATO plus MEL decreased these indices compared to the diabetic and ATO groups. Histologically, retinal vascular congestion was not observed in the combined ATO and MEL group as compared to the diabetic, ATO, and MEL groups. These data provide evidence for the therapeutic value of MEL in combination with ATO in clinical practice for prevention of DR.