Herb Drug interaction is a challenging concept, since the consumption of herbal and other drugs is not documented in patient’s profile. With this aspect the present study was designed to investigate the pharmacokinetic and Pharmacodynamic effect of neem leaf extract (NE) on the pharmacokinetics and pharmacodynamics of Glimepiride in diabetic rats. All the pharmacokinetic parameters such as Cmax, AUC0-n, AUCtot, t1/2 are increased and clearance and Vd are decreased when compared with control group. In Pharmacodynamic study the blood glucose levels are estimated, total antioxidant status in diabetic rats by using DPPH method and oral glucose toleranc test were performed. Combination has improved the total antioxidant status. The results revealed that combination of Glimepiride with neem leaf extract leads to enhancement of bioavailability of Glinepiride, this suggest that neem leaf extract might be beneficial as an adjuvant to Glimepiride in diabetic patients.