Medical quality control produces enormous amounts of dangerous organic waste, which has a critical ecological impact. It was found that mixed-micellar LC was adequate for this purpose. In this study, we developed and validated a simple, accurate, and robust HPLC method for simultaneously determining Metformin hydrochloride (MET) and Dapagliflozin (DAP) in tablet dosage form and human plasma. We separated the components at 30 °C on AGILENT and C18 (150 mm and 4.6 mm). The mobile phase (Mph) was 2% glacial acetic acid: acetonitrile (85:15, v/v) at 1.0 mL/min flow rate. MET and DAP had retention times of 1.071 and 1.979 minutes, respectively, during the 5-minute run. DAP and MET showed linear responses over the 1–1000 ng/ml concentration ranges for drug assays and 50–2000 ng/ml for plasma assays. A MET LOD of 0.13 ng/ml and a DAP LOD of 0.18 ng/mL are reported for drug assay, whereas for plasma assay, MET LOD is 0.74 ng/ml and DAPA LOD is 0.28 ng/mL. Several validation parameters are calculated by the International Conference on Harmonization Guidelines (ICH), including linearity, precision, accuracy, and specificity. An eco-friendly RP-HPLC method has been constructed to develop a simple, comparatively economical, and fulfilling the aims of green analytical chemistry (GAC). According to the analysis, MET and DAP could be measured simultaneously in tablet dosage form and human plasma using the method.