Background/Objectives: An observed increase in fungal infection incidence over the past two decades underscores the limitations of conventional topical treatments for deep infections, primarily due to the skin’s stratum corneum barrier. This has driven the development of advanced topical preparations. This study evaluated the encapsulation of oxiconazole utilizing novasomes to enhance its topical delivery. Methods: Oxiconazoleloaded novasomes were synthesized by the ethanol injection technique and subsequently characterized using key physicochemical parameters, including encapsulation efficiency (EE%), vesicle size (VS), zeta potential (ZP), polydispersity index (PDI), and percentage drug release (DR%). The optimized formulation underwent comprehensive evaluation employing Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM). Moreover, its activity was evaluated through in vitro penetration studies and in vivo assessments. Results: R9 was identified as the optimal candidate, demonstrating an encapsulation efficiency of 94.63 ± 1.60%, a vesicle size of 174 ± 1.15 nm, a zeta potential of −46.5 ± 1.61 mV, a polydispersity index of 0.184 ± 0.01, and a drug release rate of 51 ± 0.50% within 8 h. This optimal formula achieved 94 ± 1.75% permeation of oxiconazole within 24 h. FTIR examination affirmed the interaction of oxiconazole and the excipients, while DSC analysis verified the thermal durability of oxiconazole. In vivo histopathological examination demonstrated the superior efficacy of the optimal formula in treating Candida albicans infection. Conclusions: Novasomes emerge as a promising and efficacious system for oxiconazole encapsulation, holding significant potential for the effective and prolonged management of topical fungal infections.