This investigation examined a Roxithromycin-loaded nanosponge gel intended for topical delivery, to enhance the drug’s solubility in an aqueous medium and maintaining its presence in the intended area of treatment. Roxithromycin is categorized within BCS category II compound, combining low water solubility with high permeability. Seven distinct formulations were produced using ethyl cellulose by the emulsion–solvent diffusion technique and assessed using physicochemical tests. Preliminary analysis identified a wavelength of maximum absorption (λmax) of 210 nm; the calibration response was linear from 1–5 µg/mL (R² = 0.9989). FTIR findings supported suitability of the polymer for use with the drug. Formulation F5 had a Particle size average 382.1 nm, a polydisperse index of 0.483, and with a corresponding zeta potential value of −41.9 mV; its nanosponge dispersion released 86.0% by 7 h. The nanosponges were subsequently dispersed in Carbopol 934 gel. The optimized F5 gel contained 89.10% drug and showed diffusion rising from 21.46% at 1 h to 83.2% at 7 h. Its release profile fitted the first-order model most closely (R² = 0.9977). Against Staphylococcus aureus, the gel produced a 3.4 cm inhibition zone. No visible irritation was reported during the 14-day observation period, and the measured stability parameters showed no notable change under the storage conditions tested. Taken together, the findings support further investigation of this nanosponge gel as a topical formulation with sustained Roxithromycin release and antibacterial activity.