Background and purpose: Diabetes mellitus is one of the most common endocrine diseases. Nowadays, there is a growing interest in the study of the antidiabetic effects of herbal plants. Previous studies have confirmed the antidiabetic effects of Citrullus colocynthis. However, this study aimed at investigating the effect of the different concentrations of Citrullus colocynthis fruit on the histological alterations in normal and diabetic male rats.Materials and methods: In this experimental study, diabetes mellitus was induced by subcutaneous injection of streptozotocin (50 mg/kg). Normal and diabetic rats were daily fed by the 1%, 2% and 5% Citrullus colocynthis fruit powder concentrations in their basic and usual diet for 4 weeks. Then, the rats were anesthetized and the kidney, liver, stomach, and pancreas tissues were obtained by slash surgical and stained by H& E method for histological studies.Results: Considerable positive effects were observed in the slides of kidney, stomach, pancreas and liver tissues in the diabetic rats fed with 5% concentration of Citrullus colocynthis fruit powder. In kidney cortex, abnormal width in the Bowman's capsular space, segregation of parietal cells and cellular infiltration were improved. Sinusoidal wide spaces between hepatocyts in the liver were also disappeared and epithelium naps staved in segments of stomach mucus recovered, too. Moreover, in pancreas, the bright corona at lobule centre indicating the evacuation of acinocyts changed to normal state.Conclusion: The results of the present study indicated that the consumption of 5% concentration of Citrullus colocynthis fruit in diabetic rats had beneficial therapeutic effects on improving the signs of diabetes.