The aim of this study was to develop a fast RP-HPLC method for simultaneous measurement of two antidiabetic formulations (vildagliptin + remogliflozin and teneligliptin + remogliflozin) under identical experimental conditions. Using the Box–Behnken approach and response surface design, the interaction and quadratic influence of three variable parameters, acetonitrile %, pH of the mobile phase, and flow rate, on resolution between the peaks were optimized. To forecast the resolution of peaks (2.7 and 6.5) for the three anti-diabetic medications, the design space with desirability function was used to find the optimal chromatographic conditions. Isocratic elution with 58:42 acetonitrile and phosphate buffer (20 mM KH2PO4, pH adjusted to 4.9 with orthophosphoric acid) over a Zorabx C18 HPLC column with a flow rate of 1.2 mL min−1 separated all three analytes in 2.5 min. In addition, the optimized HPLC process was validated using ICH recommendations. The devised HPLC method’s precision and accuracy were proven by the low percent relative standard deviation (0.60–1.65%), good percentage recovery (98.18–101.50%), and low percentage relative errors (0.20–1.82%). The method’s robustness was also proven by slightly varying the five separate parameters. Finally, the accuracy of the proposed HPLC approach was confirmed using a standard addition method for simultaneous determination of vildagliptin + remogliflozin and teneligliptin + remogliflozin from formulations. Furthermore, the findings demonstrated that experimental design can be successfully used to optimize chromatographic conditions with fewer runs. The devised HPLC method for simultaneous quantification of two binary combinations utilizing the same chromatographic conditions is fast, accurate, precise, and easy, and it might be utilized in laboratories for routine quality control investigations on both formulations.