Allergic rhinitis is one of the most overlooked mismanaged diseases. The present study aimed to formulate fluticasone propionate zein nanoparticles (FP-ZNPs) in situ gel to enhance FP poor aqueous solubility, increase its residence time in the nasal cavity and improve its nasal drug absorption and healing rates. 23 full factorial design was constructed to study the influence of three factors on the prepared FP-ZNPs; zein: drug ratio, pH of the aqueous media, and stabilizer type and the responses were particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). Two thermosensitive polymers were used to prepare in situ gels loaded with the optimized FP-ZNPs formulation using response surface methodology. Gelling time, temperature, viscosity, in vitro release, ex vivo permeation, and in vivo histopathological studies were investigated. The optimized FP-ZNPs formulation (FP-ZNPs 4) showed PS of 300.6 ± 32.9 nm, ZP of −32.6 ± 2.3 mV and EE of 98.8606 ± 0.0029 %. FP-ZNPs in situ gel (FP-ZNPs-gel 5) showed gelling time of 54 ± 2 s and temperature of 30 ± 0.1 °C. In vitro release and ex vivo permeation of FP-ZNPs 4 showed superior performance over FP dispersion. Histopathological examination of the male albino rats’ nasal mucosa showed almost complete healing after 7 days of treatment with FP-ZNPs 4 and FP-ZNPs-gel 5 than Flixonase® with significant suppression in MMP9 levels. In conclusion, FP-ZNPs is proposed as a significantly advanced intranasal dosage form than the marketed product with higher healing rates, better treatment protocols and less patient complications.