The present investigation aimed to develop novel voriconazole nanosuspension loaded topical in situ gel for the management of serious fungal infections by virtue of modified cold approach. The solvent evaporation approach was applied for generating the voriconazole nanosuspension and was assessed for particle-size, particle distribution index, zeta potential, entrapment efficiency, saturation solubility, FTIR, DSC. Then the loading of voriconazole nanosuspension to form in situ gel for topical release was effectively achieved employing 32 factorial design that optimized the process. Developed in situ gel was assessed for various parameters like appearance and pH, in vitro gelation, viscosity, sterility testing, skin permeation as well as retention analysis, in vitro antifungal activity, and stability. The poloxamer based gelling system was found to be clear and transparent with +++ gelation capacity with 240 cps viscosity (batch F8). Nanosuspension-loaded in situ gel encompassing poloxamer-188 and HPMC-E15 demonstrated enhanced antifungal activity against Candida albicans as compared to pure drug voriconazole. The present study concludes that voriconazole nanosuspension loaded in situ topical gel employing poloxamer-188 as well as HPMC-E15 act as a potential remedy for serious fungal infections.