The present work is concerned with development, optimization and validation of two chromatographic methods for the simultaneous determination of nadifloxacine (ND) and mometasone furoate (MF). The first developed method was RP-HPLC depended on chromatographic separation using Phenyl-hexyl column and a mobile phase composed of acetonitrile: acidified water with orthophosphoric acid up to (pH 2.5 ± 0.1) in the proportion of (65: 35 v/v) pumped at a flow rate of 1.25 mL min−1. All measurements were performed with UV detection at 254 nm. The second method was TLC-densitometry, chromatographic separation was established on aluminum TLC plates pre-coated with silica gel GF254 as the stationary phase and chloroform: methanol: hexane: ethyl acetate: acetic acid (9: 1: 3: 3: 0.1, by volume) as the mobile phase followed by densitometric measurement of the separated bands at 254 nm. Validation of the suggested methods was successfully applied with respect to ICH guidelines. The proposed chromatographic methods were used to determine both drugs binary mixture in pure form and dosage form. The proposed methods give good linearity in the range 0.5‒5.0 μg/mL and 0.5‒40 µg/spot for HPLC and HPTLC methods, respectively. While MF standard solutions in the range 0.2‒1.2 μg/mL and 0.5‒3.8 µg/ spot for HPLC and HPTLC methods, respectively. The obtained results were statistically compared with those achieved by the reported methods, showing no significant difference with respect to accuracy and precision at p = 0.05.