Green analytical chemistry is an innovative approach to making analytical experiments more environmentally friendly, safer for humans, and less toxic to the environment by utilizing eco￾friendly reagents and chemicals. Diabetics are twice as likely to experience hypertension compared to nondiabetics. Individuals with both conditions face a significantly increased risk of early microvascular and macrovascular complications. Regular monitoring helps ensure the drug concentration remains within the therapeutic range, maximizing its effectiveness. Herein, a high-performance liquid chromatographic (HPLC) method is provided to evaluate and isolate the studied drugs in the presence of their toxic impurities. The study involves the simultaneous administration of two crucial drugs: the antidiabetic metformin and the antihypertensive bisoprolol. We have investigated their pure form in spiked human plasma, as well as their interaction while their possible toxic impurities are present as melamine and cyanoguanidine. The optimal conditions were achieved using a mobile phase consisting of 0.1 M SDS, 0.1% ortho-phosphoric acid in water, and 10% isopropanol at a flow rate of 1.0 mL/ min. The pH was adjusted to 5.0 using triethylamine, and the column temperature was maintained at 25 °C on a symmetry C18 column (Kinetex 1.7µ C18 100A, 2.1-mm×50-mm), with detection at 230 nm. Following the International Conference of Harmonization guideline, the method was successfully validated within the linearity range of 1–25 µg/mL for metformin and bisoprolol. Notably, the LOQ was determined to be 0.92 µg/mL for metformin and 0.54 µg/mL for bisoprolol. The established method epitomizes accuracy, cost-effectiveness, selectivity, and reproducibility. The evaluation of the suggested approaches’ level of greenness was meticulously conducted using a variety of assessments, including the Analytical eco-scale system, the Modified Green Analytical Procedure Index (MoGAPI), The Analytical Green Star Area (AGSA), Blueness evaluation using BAGI tools, Carbon footprint (CaFRI), Click Analytical Chemistry Index (CACI) and White analytical chemistry (WAC).