Despite the antidepressant potency of paroxetine, its side effect of erectile dysfunction is burdensome. Grapefruit peels (GFPs) are underutilized cultivar wastes with wide range of therapeutic potentials which have been attributed to their antioxidant behavior and phenolic contents’ abilities to effectively inhibit enzymatic activities and manage endothelial dysfunction in cardiovascular disorders. This study aims to investigate the erectogenic potentials of GFP extract in a rat model of paroxetine-induced ED. Experimental rats were sectioned into five groups: [1: control; 2: paroxetine (10 mg/kg); 3: paroxetine + sildenafil (5 mg/kg); 4: paroxetine + GFP (50 mg/kg); 5: paroxetine + GFP (100 mg/kg)] and treated for 28 days. Sexual behavior of rats was assessed and effect of GFP on ecto-5′ nucleotidases, phosphodiesterase-5, and adenosine deaminase (ADA) activities was determined in rats’ penile tissues. The levels of malondialdehyde, nitric oxide (NO) as well as superoxide dismutase (SOD) and catalase activities were also determined. HPLC-DAD analysis showed the presence of naringin, rutin, caffeic acid, quercitrin, quercetin, and kaempferol glycoside. Oral administration of paroxetine reduced erectile response as revealed by their low intromission and mounting numbers as well as high intromission and mounting latencies. Paroxetine caused a significant elevation of ADA and phosphodiesterase-5 activities and malondialdehyde levels with drastic reduction in levels of NO, SOD, and catalase activities in rats’ penile tissues. However, GFP extract reversed PDE-5, ADA, and antioxidant activities to normal levels, raised the concentration of NO. These results suggest the erectogenic effects and protective potentials of GFP extract against paroxetine-induced erectile dysfunction. PRACTICAL APPLICATION: Grapefruit peels are an environmental menace in many countries and this study showed that the peels can be used in the prevention / management of erectile dysfunction. The therapeutic potentials of the peels are due to the presence of bioactive compounds such as flavonoids and phenolic acids. Therefore, exploring the erectogenic potentials of the peels will translate to conversion of the wastes to therapeutic products.© 2022 Wiley Periodicals LLC.