Various antidiabetic combinations have recently been used to improve the management of type II diabetes mellitus. The first time a totally green mixed micellar LC method was used to analyze the biguanide metformin (MET) in a mixture with two sulfonylurea antidiabetics, glipizide (GPZ) and glimepiride (GLM), as well as pioglitazone (PGZ) as a thiazolidinedione derivative antidiabetic and repaglinide (RPG) as an insulin secreta- gogue antidiabetic. Response surface methodology (RSM) was used to optimize the method by using central composite design (CCD). The design space that represents the robustness zone was identified. Analytes were separated by elution of an aqueous mobile phase containing Brij-35 (12.05 mM) and SDS (76.25 mM) at pH 3.72 on a Symmetry C18 column (75*4.6 mm, 3.5 m) at a flow rate of 1 mL/min and UV detection at 225 nm and 210 nm, respectively, for MET and the other analytes. The laboratory mixtures and pharmaceutical products of the examined drugs were successfully determined using the established method. Using the Green Analytical Pro- cedure Index (GAPI) and Analytical Greenness Metric (AGREE) principles, the greenness of the created method was analyzed and compared to previously reported methods. In comparison to previous methods, the new method was shown to be more efficient and effective