Mirtazapine is an antidepressant with prominent antioxidant effects. Chrysin, a natural flavone, exhibits multiple pharmacological actions. This study was designed to investigate the potential protective effects of chrysin and mirtazapine against nitrofurazone-induced testicular damage in rats. Possible underlying mechanisms such as oxidative stress, inflammation and apoptosis were also investigated. Testicular damage was induced by oral administration of nitrofurazone (50 mg/kg/day) for two weeks. Chrysin (25 and 50 mg/kg/day, p.o.) and mirtazapine (15 and 30 mg/kg/day, p.o.) were applied for three weeks, starting one week before nitrofurazone administration. Prophylactic treatment with chrysin and mirtazapine attenuated the elevation of serum acid phosphatase enzyme activity and halted the decline of sperm count and sperm viability resulted from nitrofurazone administration. Moreover, both agents ameliorated nitrofurazone-induced lipid peroxidation, glutathione depletion, elevation in tumor necrosis factor-α level and reduction in c-kit level in rat testes. With respect to apoptosis, immunohistochemical analysis revealed that chrysin and mirtazapine reduced the expression of caspase-3 in testicular tissue which was induced by nitrofurazone. Histopathological findings further supported the protective effects of both drugs against nitrofurazone-induced testicular injury. These findings suggest that the cytoprotective effects of chrysin and mirtazapine on rat testes were associated with suppression of oxidative stress and apoptotic tissue damage. Generally, chrysin prophylactic treatment showed a superior testicular protection than mirtazapine at the tested doses.