In this study, we investigated the effects of pomegranate on alleviating cyclophosphamide-induced hemorrhagic cystitis (HC). Initially, 16 Sprague-Dawley rats were allocated into 4 groups: group 1 (control), group 2 (CP) in which HC was induced by cyclophosphamide; group 3 (CP+M), HC-induced rats that received Mesna regimen, and group 4 (CP+P), which compromised rats that had been on a 14-day diet of pomegranate juice before HC induction. Cystometry was performed a few hours before euthanasia; after euthanasia, aortic blood samples and bladder tissue samples were obtained to perform TUNEL assay, and histopathologic and biochemical assessments. Urodynamic findings revealed that mean detrusor pressure in CP+P was significantly lower compared with that in CP and CP+M (P<0.05). Histopathologically, urothelium destruction and inflammation were lower in CP+P and CP+M compared with that in CP. Collagen destruction was less prominent in CP+P compared with that in CP and CP+M. Tissue and plasma levels of malondialdehyde were significantly lower in CP+P versus CP (P<0.05). Catalase activity and total protein thiol group levels in plasma and bladder tissue were higher in CP+P versus CP (P<0.05). The TUNEL positivity in CP+P was significantly weaker than that in CP, indicating less DNA fragmentation and apoptosis. Pomegranate's characteristics could significantly affect the inflammatory and destructive process of hemorrhagic cystitis.