Tinospora cordifolia aqua-alcoholic extract (TCE) with metformin (MET) has been shown to be significantly more effective against clinical diabetes-associated disorders. Since there is insufficient clarity behind this, pharmacokinetic interaction was investigated to unravel the mechanism partly. A significant increase in area under the curve (AUC0-∞), half-life (T1/2), and decrease in renal clearance (CLr) of MET was observed in animals dosed with TCE (100 mg/Kg) for 14 days. However, no significant change was observed in the time to reach maximum concentration (Tmax), indicating that TCE selectively affects the CLr of MET. Many TCE’s cationic components/metabolites showed a relatively higher potential affinity for organic cationic transporter 2 (OCT2), which partly justifies the selective pharmacokinetic interaction of MET with TCE. In conclusion, TCE enhances the bioavailability of MET by reducing its renal clearance. This partly explains the basis of TCE as a complementary therapy, which requires further validation.