Two green sensitive spectrofluorimetric methods at nanogram scale were investigated for the determination of rupatadine fumarate (RUP) [method I] and its binary mixture with montelukast (MKT) [method II]. Method I is concerned with measuring the native fluorescence of RUP in presence of 0.10 M H2SO4 and 0.10 % w/v sodium dodecyl sulfate at 455 nm after excitation at 277 nm. The linearity range of the first method was 0.20-2.00 µg/mL with detection and quantitation limits of 11.00 ng/mL and 36.00 ng/mL, respectively. The second method includes the concurrent estimation of RUP and MKT in their co-formulated tablet preparation by applying first derivative synchronous spectrofluorimetric technique. The derivative intensities were measured for the two drugs in aqueous solution containing Mcllvaine’s buffer pH 2.60 at fixed wavelength difference (Δλ) of 140 nm. Each drug was estimated at the zero contribution of the other. For RUP, the intensity was measured at 261 nm while MKT was quantitated at 371 nm. The method was linear over the range of 0.10-4.00 µg/mL and 0.20-1.60 µg/mL with limits of detection 4.00 and 5.00 ng/mL and limits of quantitation 13.38 and 15.00 ng/mL for RUP and MKT, respectively. The method was extended to determine the two analytes in laboratory-prepared mixtures and combined tablets. Validation of the two methods was performed according the official recommendations of the International Council of Harmonization (ICH). Statistical interpretation of data revealed that our results were in good agreement with the comparison method. Moreover, the greenness of the methods has been assessed and confirmed by applying three different reported assessment tools.