Purpose <p>Atopic dermatitis is a condition, wherein the outermost skin layer is disrupted, leading to excessive water loss and cutaneous lesions. This study assesses an antifungal topical formulation utilizing a vesicular system loaded with ketoconazole and a hydrating agent to treat fungal skin infections while preventing resistance and recurrence.</p> Methods <p>The Central Composite Design in Design Expert software was used to optimize ketoconazole-loaded niosomes, with vesicle size and drug entrapment efficiency as dependent variables and surfactant and organic solvent concentrations as independent variables. The optimized formulation was evaluated against predicted values, and compatibility and stability were analyzed via FT-IR and differential scanning calorimetry. Niosome morphology was examined using light microscopy and SEM. Niosomes were incorporated into a hydrogel containing 5% carbamide, a pH stabilizer, and preservative to enhance dermal bioavailability. The gel underwent evaluations for viscosity, antifungal activity, <i>in vitro</i> drug release, <i>ex vivo</i> permeation, skin irritation, TEWL, and histopathology.</p> Results <p>Optimized niosomes had a vesicle size of 275&#xa0;nm and 98.38% drug entrapment efficiency. The gel was translucent, non-sticky, had a viscosity of 18,200&#xa0;mPa·s at 20&#xa0;°C, and exhibited a sustained <i>in vitro</i> drug release. The release kinetics followed zero-order and Baker-Lonsdale models, with R² values of 0.94 and 0.99. Application on mice reduced moisture loss and improved skin barrier function.</p> Conclusion <p>The ketoconazole-loaded niosomal gel is a promising carrier for dermal drug delivery against fungal infections.</p> Graphical Abstract <p></p>