Introduction: Antidepressants are commonly used in the treatment of depression and several other mental health disorders. Since antidepressants are known to cause a variety of side effects, their adverse effects on reproductive health are a matter of great concern because of the raising trend of infertility in current scenario. Aim: The present study has therefore been conducted to evaluate the effects of fluoxetine, an antidepressant, on the reproductive health of the normal and depressed mice by evaluating its adverse effects on the testis. Methods: Twenty-four adult male mice of Swiss strain were distributed into four groups of six each (n=6). Group I served as control while groups II, III, and IV received reserpine (RES: 0.75mg/kg/BW/day) for 14 days, fluoxetine (FLX: 40mg/kg/BW/day) only for 28 days, and reserpine+fluoxetine (RES treatment for 14 days followed by FLX treatment for 28 days), respectively. Results: RES as well as FLX exposure did not cause any alteration in the testicular weight, histopathology, daily sperm production, germ cells apoptosis, oxidative stress, activities of steroidogenic enzymes, and the levels of serum cholesterol, testosterone, estradiol, and prolactin except that of the plasma corticosterone which was increased significantly only in RES-exposed mice, compared with the control. By contrast, RES+FLX treatment resulted in marked regressive histopathological alterations in the testis indicated by thickened tunica propria, and vacuolized germ cells in the disorganized seminiferous tubules. Leydig cells also appeared diffused. Moreover, significant reductions were noticed in daily sperm production, the activities of steroidogenic enzymes, levels of serum testosterone, estradiol and plasma corticosterone while significant increase was noted in the levels of serum cholesterol and prolactin. Mice of this group also showed significant increase in the activity of superoxide dismutase and level of lipid peroxidation, while significant decrease in the activities of catalase, glutathione peroxidase, and the level of nitrate, compared with the control and RES-exposed mice. Further, the percentage of necrotic, early, and late apoptotic germ cells was significantly increased while that of live cells decreased significantly in the testis of such mice, compared with the control and RES-exposed mice. Conclusion: The findings of the present study therefore, indicate the spermatogenic inhibition only in RES+FLX- treated mice by causing oxidative stress, as a result of an enhanced apoptotic activity, alterations in the levels of cholesterol, and the measured hormones.