Cost-effective, green, simple and reliable transmission Fourier-transform infrared (FTIR) spectroscopic method was developed for simultaneous analysis of hypoglycemic drugs in their binary mixtures for the first time. The FTIR method was applied for the determination of vildagliptin (VILD), glimepiride (GLIM) and pioglitazone (PIOG) in binary mixture with metformin (METF). The method was validated according to the International Conference on Harmonization (ICH) guidelines. The obtained results (expressed in peak areas) are linear with concentration in the range of 0.61–20, 0.26–24 and 0.37–4 μg/mg for VILD, PIOG and GLIM, respectively while the linearity ranges for METF were 0.40–200, 0.26–800 and 0.19–1000 μg/mg with VILD, PIOG and GLIM, respectively. The limits of detection (LODs) were 0.20, 0.08 and 0.12 μg/mg for VILD, PIOG and GLIM, respectively while METF LODs were 0.13, 0.08 and 0.06 μg/mg with VILD, PIOG and GLIM, respectively. The FTIR method has been successfully applied for the determination of the cited binary mixtures in its pharmaceutical tablets and the obtained results showed satisfactory % recovery.