Erectile Dysfunction (ED) is the most common sexual dysfunction in men and is characterized by the inability to achieve or maintain an erection satisfactory for sexual intercourse. Normal erectile function is highly dependent on testosterone so any dysfunction in testosterone production may accelerate ED pathogenesis. Hypogonadism is a direct cause of ED and is characterized by the diminishing functionality of the testes in producing testosterone. Other pathological conditions such as obesity and diabetes, share similar complications of ED due to decreased testosterone levels. Furthermore, these conditions exhibit increased oxidative stress. Decreased testosterone can weaken antioxidant defenses and increase oxidative stress that then leads to endothelial dysfunction by reducing nitric oxide bioavailability and increasing fibrosis which ultimately leads to ED. Current therapies for ED do not directly target antioxidant defenses to reduce oxidative stress damage. Two prospective drugs, Resveratrol and Mitoquinone (MitoQ), have antioxidant properties that limit oxidative stress and may improve erectile function. They have shown to be successful in decreasing oxidative stress damage and improving endothelial function in cardiovascular disease models, so the objective of this study was to explore the effect resveratrol and MitoQ has on antioxidant defense gene expression and erectile function in a model of hypogonadism. We hypothesized that resveratrol and MitoQ treatment will improve antioxidant defenses and improve erectile function. In this study, we used a surgically castrated mouse model to induce ED. We treated mice with resveratrol or MitoQ for eight weeks. Following treatment, we sacrificed and harvested mice corpus cavernosum (CC). We measured the expression of genes related to antioxidant defenses by performing qRT‐PCR. Additionally, ex vivo vasoreactivity of the internal pudendal artery (IPA) and CC were assessed in response to concentration ranges of multiple agonists with DMT myograph system. One‐way ANOVA and Two‐way ANOVA, respectively, was used to compare differences between groups. Upon castration, vasorelaxation of the IPA and CC significantly declined. Antioxidant defenses were reduced with castration as seen by reduced expression in: Gclc, Gpx1, Prdx3, Prdx5, Nqo1, SOD2, SOD3, and Hmox1. After treatment, vasorelaxation did not improve however there were improvements in antioxidant gene expression. Resveratrol significantly increased expression of Gstm, CAT, SOD1. Additionally, MitoQ and resveratrol trended to increase several antioxidant genes. There was a partially restoration of Gpx1, Prdx3, Nqo1 and SOD2 levels and Hmox1 was restored back to sham levels. To conclude, neither long‐term administration of MitoQ nor resveratrol improved relaxation responses of the IPA or CC, however, they were able to stimulate and improve antioxidant gene expression. Even though these drugs were unable to improve erectile function on their own, they may be paired with other treatments such as PDE‐5 inhibitors, to ...