This study developed a green, highly sensitive, and accurate spectrofluorimetric method for the simultaneous determination of Montelukast sodium (MTK) and Bilastine (BIL) in pharmaceutical formulations. The method utilizes the first derivative of synchronous fluorescence at a fixed wavelength difference (Δλ) of 110 nm, with peak amplitudes at 381 nm for MTK and 324 nm for BIL. The method was validated using International Council on Harmonization (ICH) guidelines, showing linearity over concentration ranges of 50–2000 ng mL⁻¹ for MTK and 50–1000 ng mL⁻¹ for BIL. The limit of detection (LOD) was 16.5 and 10.9 ng mL⁻¹ for MTK and BIL, respectively, and the limit of quantification (LOQ) was 49.9 and 33.0 ng mL⁻¹. The method was successfully applied to quantify both drugs in synthetic tablet mixtures and laboratory-prepared mixtures with varying ratios. The results were compared with published methods using F-test and t-test, showing no significant differences. The method was also evaluated for its environmental friendliness using the Eco-scale, Green Analytical Procedure Index (GAPI), and Analytical Greenness Calculator (AGREE), all indicating its green and sustainable nature. The developed method is ideal for quality control due to its simplicity, sensitivity, and low environmental impact.This study developed a green, highly sensitive, and accurate spectrofluorimetric method for the simultaneous determination of Montelukast sodium (MTK) and Bilastine (BIL) in pharmaceutical formulations. The method utilizes the first derivative of synchronous fluorescence at a fixed wavelength difference (Δλ) of 110 nm, with peak amplitudes at 381 nm for MTK and 324 nm for BIL. The method was validated using International Council on Harmonization (ICH) guidelines, showing linearity over concentration ranges of 50–2000 ng mL⁻¹ for MTK and 50–1000 ng mL⁻¹ for BIL. The limit of detection (LOD) was 16.5 and 10.9 ng mL⁻¹ for MTK and BIL, respectively, and the limit of quantification (LOQ) was 49.9 and 33.0 ng mL⁻¹. The method was successfully applied to quantify both drugs in synthetic tablet mixtures and laboratory-prepared mixtures with varying ratios. The results were compared with published methods using F-test and t-test, showing no significant differences. The method was also evaluated for its environmental friendliness using the Eco-scale, Green Analytical Procedure Index (GAPI), and Analytical Greenness Calculator (AGREE), all indicating its green and sustainable nature. The developed method is ideal for quality control due to its simplicity, sensitivity, and low environmental impact.