Background: Despite numerous reports regarding the associations of Khat chewing with serious health adverse effects, a significant number of people worldwide uses Khat daily, especially in its origin countries. The risk of co-administration of Khat and drugs that is high among these individuals, leading to increase probability of adverse Khat-drug interactions. Under these circumstances, it becomes important to evaluate the effect of concomitant administration of Khat and clinical drugs. Metformin is a drug of biguanide class used to the lower blood glucose concentrations in patients with type 2 diabetes mellitus (T2DM). Aim and Objectives: The aim of the study was to evaluate the beneficial or harmful effects of concomitant administration of Khat and metformin in a high fructose diet induced T2DM model. Materials and Methods: Thirty-six adult male rats weighing 120150 g were made diabetic by feeding a high fructose diet for 4 weeks. These rats while continuing to be on high fructose diet were divided into six groups and administered orally, normal control (normal saline), normal control with Khat (1500 mg/kg), non-treated diabetic group, Khat treated group (1500 mg/kg), metformin treated diabetic (300 mg/kg), and metformin (300 mg/kg) with Khat (1500 mg/kg) treated group. All the above treatments were given for 4 weeks and their effects were studied. Results: The hyperglycemia, body weight, and lipid profile parameters were brought down significantly by Khat and metformin (P < 0.05) monotherapy; metformin being more effective than Khat. The metformin-Khat combination had a synergistic effect and resulted in much greater efficacy in ameliorating the parameters. Moreover the adverse effect of Khat like lowering of high-density lipoprotein cholesterol (HDL-C) levels was significantly mitigated by metformin-Khat combination. Conclusion: The results suggested that metformin-Khat combination had a much greater efficacy with the added advantage of reducing the adverse effects.