Luliconazole is a potential prescription candidate drug for the treatment of topical fungal infections. However, it has water solubility and skin permeability limitations. To overcome these limitations, a niosomal gel of luliconazole was formulated using Span 60, cholesterol, and chloroform to improve its bioavailability and to reduce its toxicity. Niosomes were analyzed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) for morphological and spectral studies respectively. The formulations had ideal nanometric vesicle sizes, encapsulation efficiency (88.891% ± 0.0364%), Zeta potential (-40.1 mV), and storage instability was not observed. The sustained-release profile of niosomal gel was observed for up to 24 h. The highest R value was 0.913; the Higuchi model was considered the best fit model for the niosomal formulations. Cytotoxicity studies confirmed the biocompatibility of the niosomal gel of luliconazole. Based on the results, it can be concluded that niosomal luliconazole may enhance the activity of luliconazole against ().