Experimental design methodology (DOE) surpasses traditional (one variable at a time) approach in improving the chromatographic separation performance with minimum effort and resources. Since combination therapy of oral hypoglycemic drugs was generally recommended by Clinical Practice Guidelines on hypoglycemic agent therapy for treatment of type 2 diabetes mellitus, DOE was adopted in development of an ion pair RP-HPLC method for the simultaneous determination of metformin hydrochloride (MET), alogliptin benzoate (ALO) and repaglinide (REP) in combined binary tablets. Screening using Plackett-Burman design followed by face centered composite design enabled the estimation of optimum settings that accomplish the most appropriate resolution and adequate peak shape within suitable run time. The designed models were statistically analyzed, graphically presented by surface plots and the relationships between coefficients of the derived polynomial equations were interpreted. The models fitted data adequately and could be used for response prediction. Chromatographic separation was achieved using Inertsil ODS column (250 mm, 4.6 mm, 5 μm), acetonitrile: phosphate buffer (0.01 M, adjusted to pH 2.5 with o-phosphoric acid): 0.3% sodium heptane sulfonate in water (60:20:20, v/v/v) as a mobile phase at flow rate 1 mL min−1. UV detection was carried out at 220 nm. Sharp and well separated peaks for the cited drugs were obtained. Laboratory prepared mixtures containing MET, ALO and REP were analyzed with mean percentage recoveries 99.66 ± 0.468, 99.98 ± 0.398 and 99.70 ± 0.988, respectively. The method was successfully applied for the determination of the drugs in binary tablets with good recoveries of 99.75 ± 0.6 and 99.74 ± 0.982 for MET and ALO tablets and 99.76 ± 0.619 and 100.08 ± 1.159 for MET and REP tablets. Method validation was performed according to ICH guidelines Q2 (R1). Robustness was evaluated using the created models. The greenness profile of the developed method was evaluated using the analytical Eco-scale and Green Analytical Procedure Index as assessment tools. The developed method proved to be accurate, selective, precise and ecofriendly procedure for the determination of the cited drugs in binary tablets and could be applied in quality control laboratories for routine analysis of the drugs.