Background: Prostate Cancer (PCa) is defined as a major health problem facing the male population. Aims: We aimed to investigate the protective effects of Orange Peel Extract (OPE) and/or selenium (Se) on chronic non-bacterial prostatitis in a rat model. Methods: Fifty-six adult male Wistar albino rats were castrated; after 5 days, they were divided randomly into eight groups (n= 7). The control group received saline treatment; while 17β-estradiol (E2) (0.25mg/kg) was injected subcutaneously in rats from Groups V, VI, VII, and VIII to induce chronic non-bacterial prostatitis. They were then treated with OPE (400mg/kg body weight; Groups II, IV, VI, and VIII) and/or sodium selenite (0.5mg/kg body weight; Groups III, IV, VII, and VIII) for 30 days. Interleukin-2 (IL2) and Prostate Cancer Antigen 3 (PCA3) mRNA expressions were determined using qPCR; Prostate-Specific Antigen (PSA) protein expression was determined immunohistochemically. Prostate tissue histology was examined by hematoxylin and eosin staining, and the levels of oxidative stress markers and antioxidant enzymes were measured. Results: E2 administration significantly increased IL2 and PCA3 mRNA expressions, and PSA protein expression. It also increased the prostate wet weight and body weight, and lipid peroxidation, nitric oxide, TNF-α, and IL-1β levels, decreased the glutathione and antioxidant enzyme levels, and caused distinct histological alterations in the prostate gland. OPE and/or Se markedly improved all the studied parameters due to their antioxidant properties and anti-inflammatory effects. Conclusion: OPE and Se showed protective effects against 17β-estradiol-induced chronic nonbacterial prostatitis. These results suggest that protection of chronic non-bacterial prostatitis by OPE+Se combination involves anti-oxidation, and anti-inflammation. Moreover, their synergistic mechanism was mostly achieved via the regulation of oxidative stress and inflammation processes.