The study aimed to discover the effect of Amitriptyline and Escitalopram on body weight and their effects on tissues of the testis and epididymis. These drugs were hypothesized to affect fertility due to their use in the treatment of depression. A group of male mice was administrated amitriptyline and another group Escitalopram for six weeks at dose of (10 mg/kg) twice a day. Then, the tissue sections of the testis and epididymis were prepared, and histopathological revealed histological changes in the testis and epididymis. It was concluded that the use of Amitriptyline and Ascitalopram causes decrease of spermatogonia, proliferation of Sertoli cells, and a decrease in spermatid, which leads to decrease of sperm.