Evaluation of diphenhydramine in talc induced type 2 diabetes mellitus was done in Wistar rats. Oral administration of Talc (10mg/kg)carried out for 21days increased the levels of serum glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), serum creatinine, blood glucose, urea, uric acid and triglycerides (TGs), but when the animals were treated with diphenhydramine (DPH), the levels of the aforementioned biochemical parameters decreased significantly (p<0.0001). The level of serum cholesterol and high density lipoprotein (HDL) was found to be reduced in Diabetes Mellitus (DM) control and when it was treated with DPH control animals, these makers increased significantly. The study done on DM and Diphenhydramine suggests that Talc increases the blood glucose level at a dose of 10mg/kg (0.14gm) and Diphenhydramine (1mg/kg)reduces the increased blood glucose level. These finding simply that diphenhydramine may be useful in the management of talc induced diabetes.