Recently, a new formulation containing metformin HCl (MFH) and remogliflozin etabonate (RGE) has been approved for the management of diabetes mellitus. However, only one analytical method has been reported for the simultaneous determination of both the analytes. Therefore, the current study was designed to develop simple UV derivative spectroscopic and rapid RP-HPLC methods for simultaneous determination of MFH and RGE. The chromatographic separation of MFH and RGE was performed using a monolithic C18 column with an optimized chromatographic conditions carried out by full factorial Box–Behnken design model. The spectroscopic technique was based on the determination of peak amplitude of second-order derivative UV spectra at zero crossings. Further, both the methods were validated and compared statistically using Student’s-t-test and F-test, and employed for the concurrent estimation of MFH and RGE in laboratory mixed solutions and formulations. Perturbation plots and response surface models showed the effect of chromatographic parameters and the final chromatographic condition was selected from 47 solutions suggested by the desirability function. Further, UV spectroscopic and HPLC procedures showed good linearity in the range of 1–24 µg/mL and 2–150 µg/mL for RGE and 2–30 µg/mL and 5–200 µg/mL for MFH, respectively. The average percent assay was found to be 99.51% and 99.80% for MFH and 99.60% and 100.07% for RGE by spectroscopic and HPLC methods, respectively. The proposed methods were simple, accurate, precise, and rapid. Therefore, they can be used for regular quality control of MFH and RGE formulations and dissolution studies as well.