Cyclophosphamide (CP) as a widely used antineoplastic drug causes hemorrhagic cystitis (HC) mainly via induction of oxidative stress. Regarding established antioxidant potential of Satureja khuzestanica (Lamiaceae) essential oil (SKEO), we aimed to investigate its protective effects in a subchronic rat model of CP-induced HC. CP (6mg/kg/day) and SKEO (225mg/kg/day) were administered alone or in combination by gavage for 28 days. Histopathological changes were investigated by light microscopy. Plasma samples were assayed for lipid peroxidation and total antioxidant power as biomarkers of toxic stress.In the CP-treated animals, irregular mucus layer, severe hemorrhage and edema, infiltration of inflammatory cells, and accumulation of mast cells were observed. In the CP+SKEO group, a relatively normal urothelial topography with decreased number of mucosal mast cells and inflammatory cells were observed. Increased lipid peroxidation along with decreased total antioxidant capacity resulting from CP treatment was significantly recovered by SKEO co-treatment.It is concluded that SKEO protects rats from CP-induced HC by reduction of free radical-induced toxic stress. It is strongly recommended to examine SKEO in the clinic to approve its benefit in patients undertaking CP.