Background The development of sound bioanalytical liquid chromatography-mass spectroscopy (LC-MS) method(s) is of paramount importance during the process of drug discovery and development, eventually culminating in marketing approval. The use of oral antidiabetic agents has been increased significantly from past decades, and till now, no bioanalytical method is available for quantitation of metformin (MET) and ertugliflozin (ERT) in the biological matrix that can be applied in bioequivalence studies using LC-MS/MS. Objective To study the use of highly responsive simple liquid–liquid extraction method development using deuterated MET and deuterated ERT, LC-MS/MS method for gradation of MET and ERT in the rat plasma. Materials and methods The chromatographic condition involves isocratic mode using Waters XBridge C18 3.5 μ (150×4.6 mm) column. Mobile phase was 0.1% orthophosphoric acid and acetonitrile in the ratio of 80 : 20 v/v. Detection was carried out on a triple quadrapole MS employing electrospray ionization technique, operating multiple reactions, monitoring with the transitions of m/z 258.2→174.1, m/z 250.1→210.2, m/z 258.2→174.1, and m/z 260.3→210.2 for MET, ERT, deuterated MET, and deuterated ERT, respectively, in the positive ion mode. Results and conclusion The method has been validated, and the linearity was observed in the range of 10–150 ng/ml and 0.1–1.5 ng/ml for MET and ERT, respectively. For intraday and interday %RSD, the values were found to be within the acceptable limits. Recovery studies for MET and ERT obtained, mean recovery of 99.5 and 98.6%, respectively. A battery of stability studies like bench-top stability, autosampler stability, freeze-thaw stability, and long-term stability were performed. Highly responsive simple LC-tandem MS assay method was developed and witnessed for the gradation of MET and ERT in the rat plasma; the developed method was applied to pharmacokinetic studies.