Itraconazole is a broad-spectrum triazole antifungal agent used to prevent and treat fungal infections. Itraconazole is commercially available as an oral and intravenous formulation; however, its administration via these routes is associated with various side effects, such as hepatotoxicity, peripheral neuropathy, cardiac dysrhythmia, and hearing loss. The objective of the current study was to prepare a stable non-aqueous topical cream loaded with itraconazole for prolonged drug contact, improved drug permeation and penetration into skin layers, and to prevent the side effects associated with other routes of administration for improved therapeutic outcomes. The developed creams were characterized for drug content, pH, texture analysis, rheology behavior, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, ex vivo drug permeation through human cadaver skin, and stability. The lead formulations were stable over three months (the last time-point tested) during refrigeration and room-temperature storage. The cream formulation developed with 15% w/w Transcutol® P improved itraconazole permeation and deposition through the skin by 8.4- and 8.2-fold, compared to the drug solution, respectively. Thus, itraconazole -loaded non-aqueous creams can serve as alternative drug delivery platforms for the treatment of fungal skin infections over oral/parenteral itraconazole formulations.