Retinopathy is a serious complication of insulin resistance. We aimed to investigate the therapeutic effect of nebivolol and/or tadalafil on insulin resistance-induced retinopathy. Insulin resistance was induced in rats using a dietary model of a high-fructose, high-fat, high-salt diet (HFrFSD). Five groups were used in the current study: standard chow diet (SCD), HFrFSD, nebivolol, tadalafil, and their half doses combination. At the end of the experiment, markers of obesity and metabolic changes were measured; moreover, changes in retinal oxidative stress, vascular reactivity, apoptosis, fibrosis, and angiogenesis markers. Histopathological changes were also recorded. Feeding rats with HFrFSD induced obesity, insulin resistance, and retinal tissue distortions, which were associated with increased retinal oxidative stress, vasculopathy, apoptosis, and angiogenesis. Both nebivolol and tadalafil did not cause significant changes in the markers of obesity, carbohydrate, and lipid metabolism, while they significantly reduced retinal tissue histopathological and molecular changes. Interestingly, the half-dose combination of nebivolol and tadalafil significantly reduced fasting blood glucose levels and insulin resistance compared with the HFrFSD group without affecting obesity markers and lipid metabolism and showed higher protective effects against retinopathy compared with the full dose individual treatments. In conclusion, nebivolol and tadalafil synergistically ameliorate insulin resistance-induced retinopathy in rats.