Febuxostat (FXT) is useful in treating hyperuricemia and chronic gout. However, it has limited bioavailability orally due to its low solubility and short half-life. This results in the need for more frequent and larger doses, increasing the likelihood of adverse effects. Against this background, the current study was established to prepare and optimize an FXT-loaded proniosomal gel using the coacervation-phase separation method. A Quality-by-Design (QbD) methodology was used to ensure the quality of the finished product by assessing how critical process parameters and critical material attributes (CMAs) affected the proniosomal gel’s critical quality attributes. Box–Behnken design was employed to explore the effect of CMAs such as the amount of cholesterol, Span 40, and Span 60 on particle size and entrapment efficiency. The optimized proniosomes had a particle size and percentage entrapment efficiency of 193.7 ± 2.26 nm and 85.3% ± 0.89%, respectively. Scanning electron microscopy was used to examine the surface morphology of the optimized formulation. The developed formulation was also subjected to in vitro drug release and ex vivo permeation studies, which established the efficiency of the prepared proniosomal gel. Stability studies also established the fact that the prepared formulation is stable to variations in temperature for up to 6 months.