Genistein seems to have a protective and therapeutic effect on conditions associated with neovascular growth in the retina. This study investigated the angiogenesis, anti-oxidant, and anti-inflammatory effect of genistein on the retinas in ovariectomized diabetic rats. In this study, forty female albino Wistar rats were divided into four groups (n=8 per group): sham, OVX, OVX +diabetes (OVX.D), and OVX.D +genistein (OVX.D.G). OVX induced by bilateral ovaries removing and then high-fat diet (HFD) and a low dose of streptozotocin (STZ) (1 mg/kg: IP injected) was used for diabetes induction (OVX.D) with eight weeks of genistein treatment (OVX.D.G). At the end of 8 weeks, the retina was removed under anesthesia. The samples were used to measure ERK, MMP-2, VEGF, and Nf-КB by western blotting and inflammatory factors ELISA and oxidative stress. Measurements of GSH and MDA showed that OVX and specially OVX.D significantly decreased GSH and increased MDA level in the retina, but genistein reversed these effects OVX.D.G groups. Also, OVX and OVX.D significantly increased VEGF, MMP-2, p-ERK, Nf-КB, IL-1β, and TNF-α expression in the retina of OVX and OVX.D groups in comparison to the sham group(P<0.05). However, a significant reduction of these proteins was observed in the genistein-treated group (P<0.05).It can be concluded ovariectomy and subsequently estrogen deficiency caused the development of inflammation, neovascularization, and then retinopathy in STZ-induced diabetic ovariectomized rats. Based on the results, genistein administration may be the practical approach for improving symptoms and complications of ovariectomized diabetic retinopathy.