Context: Tinospora cordifolia (Willd.) Miers is an antidiabetic herb globally marketed as a single or polyherbal formulation. The pharmacological activities of T. cordifolia suggest its potential to be co-administered with commonly prescribed oral hypoglycemic drugs in the therapeutic management of diabetes mellitus. Aims: The aim of this study was to evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions of the aqueous extract of T. cordifolia (TCE) with metformin (MET), sitagliptin (SITA), and glibenclamide (GLI) in streptozotocin (STZ)-induced diabetes in rats. Settings and Design: The aqueous TCE (400 mg/kg, p.o.) was co-administered with MET (90 mg/kg, p. o.), SITA (10 mg/kg, p. o.), and GLI (1 mg/kg, p. o.) for 28 days in STZ-induced diabetes in rats. Materials and Methods: The PK parameters of the three drugs were calculated using Phoenix WinNonlin®, and PD activity was determined by estimating fasting blood glucose, liver and kidney function tests, and lipid parameters. Further, histopathological examination of pancreatic cells and estimation of pancreatic antioxidant enzymes was carried out. Statistical Analysis Used: The pharmacokinetic parameters were estimated using pharmacokinetic program WinNonlin® version 3.0 (Pharmasight corporation, Mountain view, CA). The pharmacodynamic parameters were analysed using Graph Pad prism Version 6.00 applying one-way ANOVA followed by the Tukey–Kramer post test. Results: No significant PK interaction was observed between TCE and the three oral hypoglycemics. However, a significant improvement was observed in glycemic control and the conditions associated with diabetes mellitus. In addition, no incidences of hypoglycemia were observed. Conclusion: The co-administration of TCE with MET, SITA, and GLI helped in better management of diabetes and associated comorbidities than their individual administrations. There were no significant PK interactions observed. Our findings provide insights into the safety and efficacy of the combination therapy of TCE with MET, SITA, and GLI in the management of diabetes and associated conditions.