Abstract: Background and Objective: Orlistat decreases the absorption of fat from the gastrointestinal tract by inhibiting pancreatic and gastric lipases, so encourage weight loss. Orlistat is clinically beneficial in reducing body weight in patients with Type 2 diabetes. The objective of the following study is the investigation of the influence of Orlistat in the bioavailability of selective concomitant medications for type 2 diabetes with different lipophilicity; Metformin (MT) and Gliclazide (GZ). Materials and Methods: Sprague-Dawley rats, either sex rats were selected as the animal model. The oral glucose loading animal model used for evaluation of bioavailability of both drugs GZ and MT. The effects of the concomitant intake of Orlistat with both drug as well as oily or aqueous meal evaluated through evaluation of blood glucose level lowering. Results: Orlistat affects the bioavailability of gliclazide, with high fat content-meal, p-value 0.128, on the other hand, MT not affected. The results suggest the administration of Orlistat and GZ with the presence of high-fat meals will significantly affect GZ bioavailability. Conclusion: Based on the glycaemic lowering effects of orlistat seen here. Attention must be raised for concomitant dosing of Orlistat with GZ, especially as the case of a high-fat meal for diabetic patients. More research needed to specify the time interval limit for dose delay between GZ and Orlistat.