This study aimed to prepare Posaconazole (PCZ) microsponges and formulate them into a hydrogel. The microsponges were prepared by using Design Expert’s Box Behnken Design with ethyl cellulose and polyvinyl alcohol. In this drug-polymer ratio, surfactant (PVA) and stirring speed were considered as inputs to check the entrapment and the yield as dependent variables. The so-formed microsponges were further made intoa transdermal gel. The compatibilityand physical characterization including drug release were assessed. The study revealed that variations in various parameters across different formulations, with the optimized formulation (PM-3) demonstrating desirable attributes such as smaller particle size, higher % yield, % entrapment, and superior PCZ discharge profile. SEM analysis confirmed the favorable spherical morphology and porous structure of PM-3 microsponges, indicating their suitability for PCZ loading, discharge, and interaction with the skin environment. In vitroPCZrelease studies demonstrated the effectiveness of PM-3 in providing rapid initial discharge followed by sustained discharge over 12 h, suggesting potential for optimized PCZ delivery and therapeutic outcomes. Furthermore, viscosity studies indicated that PM-3 gel exhibited higher viscosity compared to conventional gel, potentially enhancing adherence to the skin surface and improving PCZ absorption. The superior antimicrobial activity of PMG-3, as evidenced by a larger zone of inhibition in the disk diffusion assay, further underscores its potential for effective control of microbial growth. This study successfully developed PCZ microsponges converted into a hydrogel. These findings suggest the promising utility of PCZ-loaded microsponge hydrogels in treating fungal infections.