Metformin and glimepiride have been marked as potential hypoglycemic agents for the treatment of type 2 diabetes. The purpose of this study was to investigate the effect of daily oral administration of metformin (500 mg/kg) or glimepiride (0.5 mg/kg) alone or in combination for 28 days on some physiological parameters and histological alterations in liver and kidney of the diabetic rats. Diabetes was induced by a single intraperitoneal dose of alloxan (150 mg/kg) Data showed that metformin and glimepiride alone or in combination induced a significant decrease in serum glucose levels in the diabetic rats. Treating the diabetic rats with glimepiride increased the AST activity significantly. Meanwhile, administration of glimepiride or metformin had no significant effect on the activity of ALT. On the other hand, the combination of both drugs exhibited a significant reduction in the activities of AST and ALT as compared to that in the diabetic control rats. Glimepiride treatment revealed that total protein and globulin levels were increased, while metformin or the combined drug resulted in a significant decrease in albumin level which almost reached the normal value and an increase in the globulin than that of the diabetic rats. Creatinine level improved significantly in all the treated groups in comparison to that of the diabetic group and reached the normal values. On the other hand, no sign of improvement in the levels of urea was observed in the rats treated with metformin or the combined drug, while treatment with glimepiride decreased urea levels significantly. Histological examination of liver in the diabetic rats showed extensive necrosis of hepatocytes, cytoplasmic vacuolation, distended sinusoids with massive congestion. In addition, the kidney glomeruli increased in size and the renal tubules degenerated. The treatment with metformin or glimepiride ameliorated the hepatic injury, at the same time; the combined drug caused severe destruction in the liver cells. The treated rats also exhibited shrinking in the glomerular capillaries with widening of Bowman's space, mesangial matrix expansion, necrosis and vacuolation of renal tubules.In conclusion, the combination of biochemical and histological biomarkers provides useful and sensitive tools in the investigation of chronic effects induced by diabetes and anti-diabetic drugs.