Background: Duloxetine is an antidepressant that has great results in major depression. Antidepressants including duloxetine are commonly used in male patients during reproductive period without a clear data of their human reproductive toxicity in addition to the conflicting results of animal studies. Aim: this work aimed to investigate the effects of duloxetine on male fertility parameters. Methods: 54 adult male rats were randomly designated to 3 groups. Group 1 (Control) were administered 2 mL of distilled water. Groups 2 and 3 received 10 mg/kg and 50 mg/kg body weight of duloxetine respectively. Each group was further divided into 3 subgroups according to treatment duration (one month, two months and three months respectively). At the end of the study, serum testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was determined by radioimmunoassay. After sacrification of animals, parts of testes from all groups were subjected to oxidative stress analysis which includes Superoxide dismutase (SOD) and Malondialdehyde (MDA). The caudal part of the epididymis was resected for sperm collection and examination of vitality, morphology, motility and concentration. Additionally, small testicular specimens were fixed for histopathological examination. Results: Testosterone level of the high dose group (group 3) showed statistically significantly lower level than the control group. Both treated groups demonstrated significant decline in sperm concentration, motility, and viability with increased morphological abnormalities. Histopathological examination of testicular tissue of both treated groups revealed decreased number of layers of germinal epithelium and vacuolar degeneration, accumulation of degenerated cellular debris in seminiferous tubules with atrophy and misshaping of seminiferous tubules in addition to thickening of the testicular wall, necrosis of some seminiferous tubules and angiopathic changes as thrombosis of some interstitial blood vessels. Conclusion: Duloxetine might have negative impact on male fertility, further human and animal research is needed to clarify those effects.