Niosomes are a non-ionic surfactant-based vesicular system obtained via the hydration of non-ionic surfactants with cholesterol (to impart rigidity). Among various vesicular systems, the niosome provides stability, while the leakage of the drug can be avoided; so, they are considered as a suitable approach. The present study aimed to improve patient compliance in treating skin allergic reactions, and an attempt was made to create a niosomal nanogel loaded with ebastine. Thin-film hydration was used to prepare niosomes using cholesterol, Span 60, Tween 80, and ebastine; the procedure was optimized using a Box–Behnken design. A dispersion method was used, to prepare niosomal gels with carbopol 934 as the gelling agent for a more effective therapeutic result. Ebastine-loaded niosomal nanogels were prepared and evaluated for drug excipient compatibility using FTIR, which revealed that the formulation was compatible. The percentage drug entrapment efficiency was found to be 84.19 %, zeta potential was -27 mV, and vesicle size was between 100 and 300 nm. Nanogels were also evaluated to determine the pH of the gel, their in vitro drug release, and their stability;acceptable results were found. This study shows the successful development of ebastine-loaded niosomal nanogels, with improved penetration, good homogeneity, and stability. It can be concluded that ebastine-loaded niosomal
nanogels could be an effective treatment for skin allergic reactions when applied transdermally.