The quantity of impurities found in drug products determines the final product's safety. Impurities must thus be carefully monitored and managed throughout the drug development process. The objective of this study was to reveal a high-performance liquid chromatography (HPLC) method for identifying and quantifying serious nephrotoxic and skin-irritating impurities. Cyanoguanidine (CYG) and melamine (MEL) are in pharmaceutical products containing metformin hydrochloride (MTF), a widely used oral antidiabetic drug, in combination with some commonly prescribed oral antidiabetic drugs, namely, pioglitazone hydrochloride (PGT) and glibenclamide (GBC). Additionally, this study aimed to determine the ternary combination of these antihyperglycemic agents in a tablet dosage form. The separation and quantification of impurities as well as antihyperglycemic drugs were performed on a VDSpher Pur 100 C18-E (250 mm 4.6 mm, 5 μm) column using gradient elution with a mobile phase consisting of 0.1 M heptane sulfonic acid (pH 2.2) and acetonitrile. A flow rate of 1.5 mL/min was used to pump the mobile phase. A photodiode array detector (PDA) was used to monitor the ternary mixture with impurities at 225 nm. The retention times for CYG, MEL, MTF, PGT, and GBC were 1.749, 2.950, 3.640, 5.062, and 7.788 min, respectively. Molecular docking was also used to demonstrate how MEL toxicity could be shown by its attachment to several of albumin's known arachidonic acid binding sites. The green analytical procedure index (GAPI) and analytical greenness calculator reveal that the method is environmentally acceptable. The new method was tested in terms of its specificity, precision, as well as its accuracy, LOD, and LOQ. The results of the study were compared statistically to the results of the method that was reported. There was no significant difference in precision or accuracy.