To date, no effective medical approach for the treatment of erectile dysfunction (ED) secondary to ischemic priapism (IP) has been described. The aim of this study was to evaluate the anti-inflammatory, antifibrotic, and antioxidant effects of pirfenidone (PFD) on cavernosal tissue in a rat model of IP. Forty-eight male albino rats aged 8-10 months, with mean weights of 410 ± 18.6 g were randomized into four groups (n = 12 in each group): no IP (group 1); IP for 1 h, followed by intracavernosal pressure (ICP) measurements using electrical cavernous nerve stimulation (CNS) (group 2); IP for 1 h, followed by ICP measurements using electrical CNS 6 weeks later (group 3); and IP for 1 h, oral PFD (30 mg/kg once daily) treatment by oral gavage, followed by ICP measurements using electrical CNS 6 weeks later (group 4). Malondialdehyde (MDA) and reduced glutathione levels were measured spectrophotometrically. In a histological evaluation, cavernosal collagen/smooth muscle ratios were calculated. The intracavernosal pressure values of group 1 were higher than those of groups 2 and 3 (p < 0.05) but similar to those of group 4 (p > 0.05). The mean MDA level was significantly higher in group 3, as compared with that in group 4 (p = 0.004). The mean collagen/smooth muscle ratio in groups 1-4 was 24%, 42%, 65%, and 48%, respectively. Physiological, biochemical, and histopathological evaluations of the PFD effect on cavernosal tissue in a rat model of IP were the strengths and the lack of molecular and immunohistochemical analysis were the limitations of this study. In this study, we examined the effects of PFD on cavernosal tissue in a rat model of IP. We found that PFD reduced cavernosal fibrotic activity and improved erectile function. We conclude that PFD may represent a new treatment option in IP treatment.