This study evaluated the role of quercetin against cyclophosphamide‐induced distortion of rat testicular function. Adult rats were administered cyclophosphamide (100 mg/kg), quercetin (50 mg/kg) and in combination for seven days. Cyclophosphamide caused a significant increase in the activities of indoleamine 2, 3‐dioxygenases (IDO), tryptophan 2, 3‐dioxygenase (TDO), myeloperoxidase (MPO), and elevated the concentrations of interleukin 6 (IL‐6) and interferon‐γ (IFN‐γ). Cyclophosphamide increased testis malondialdehyde (MDA) concentrations but depleted superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐Px) and glutathione (GSH). However, quercetin co‐administration significantly (p < 0.05) prevented the increased values of IDO, TDO, MPO, IL‐6, IFN‐γ, MDA, SOD, CAT, GSH‐Px and GSH compared with control rats. Also, quercetin co‐treatment significantly increased serum testosterone, follicle‐stimulating hormone (FSH), prolactin, luteinizing hormone (LH), activities of testicular 3β‐hydroxysteroid dehydrogenase (3 β‐HSD), 17β‐hydroxysteroid dehydrogenase (17 β‐HSD) as well as sperm count, motility and viability but reduced abnormal sperm morphology. Quercetin exposure alone did not alter any of the parameters evaluated relative to control. Thus, quercetin protected the testes against cyclophosphamide‐induced alterations in immunosuppressive IDO/TDO activities elicited by oxidative‐inflammatory mediators.