Background <p>The rising incidence of superficial fungal infections and the limitations of conventional topical therapies necessitate the development of advanced, targeted delivery systems.</p> Objective <p>This study aimed to develop and evaluate a novel quiniodochlor (QD)-loaded nanostructured lipid carrier (NLC) gel for enhanced topical antifungal therapy.</p> Methods <p>QD-loaded NLCs were prepared by hot homogenization using stearic acid (solid lipid) and cinnamon oil (liquid lipid), stabilized with Tween^® 80, and incorporated into a chitosan hydrogel. Formulations were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), drug release, and physicochemical stability. The developed gel was further evaluated for spreadability, extrudability, ex vivo skin permeation/retention, in vitro antifungal activity against <i>Candida albicans</i>, and in vivo skin irritation.</p> Results <p>The optimized NLCs exhibited nanoscale particle sizes (141.86–250.79) high EE% (&gt; 98%), and low PDI (0.28–0.43). Despite a near-neutral zeta potential, colloidal stability was maintained, attributed to steric stabilization. The NLC gel showed a sustained drug release profile, significantly higher skin retention, and about 1.6-fold larger zone of inhibition against <i>C. albicans</i> compared to a marketed QD cream. Ex vivo studies confirmed enhanced dermal accumulation with negligible transdermal permeation. The formulation demonstrated excellent spreadability and extrudability, and elicited no signs of erythema or edema in an in vivo skin irritation model.</p> Conclusion <p>The developed QD-NLC-chitosan gel presents a promising, safe, and effective topical strategy with enhanced skin targeting, sustained local release, and superior antifungal activity, demonstrating strong potential as an advanced therapeutic alternative for superficial mycoses.</p>