Resveratrol (RES) is a potent antioxidant used for the management of several central nervous system diseases. RES bioavailability is less than 1 owing to its low solubility and extensive intestinal and hepatic metabolism. The aim of the study was to enhance RES bioavailability through developing intranasal transferosomal mucoadhesive gel. Reverse evaporation-vortexing sonication method was employed to prepare RES-loaded transferosomes. Transferosomes were developed via 3 definitive screening design, using soya lecithin, permeation enhancers, and surfactants. The optimized formula displayed spherical shape with vesicle size of 83.79 ± 2.54 nm and entrapment efficiency (EE%) of 72.58 ± 4.51%. Mucoadhesive gels were prepared and evaluated, then optimized RES transferosomes were incorporated into the selected gel and characterized using FTIR spectroscopy, in vitro release, and ex vivo permeation study. Histopathological examination of nasal mucosa and in vivo pharmacokinetic study were conducted. In vitro drug release from transferosomal gel was 65.87 ± 2.12% and ex vivo permeation was 75.95 ± 3.19%. Histopathological study confirmed the safety of the optimized formula. The C of RES in the optimized RES trans-gel was 2.15 times higher than the oral RES suspension and AUC increased by 22.5 times. The optimized RES trans-gel developed intranasal safety and bioavailability enhancement through passing hepatic and intestinal metabolism.