<p>Folliculitis, frequently associated with <i>Staphylococcus aureus</i>, remains challenging to treat due to limited skin penetration of topical antibiotics and emerging resistance. The present study aimed to develop a fusidic acid (FA)-loaded microemulsion-based gel (MEG) to enhance topical delivery and antibacterial performance. Tea tree oil, Teric 862, and Transcutol P were selected based on solubility screening, and a 2³ full factorial design was employed to evaluate their effects on droplet size and drug release. The optimized microemulsion (MEFA1) produced nanosized droplets (22.2 ± 1.2&#xa0;nm) with low dispersity and a zeta potential of − 16.2 mV. Microemulsion formation was confirmed by conductivity and dye solubilization tests, while TEM analysis revealed predominantly spherical droplets. Thermodynamic stability studies demonstrated no phase separation and minimal changes in droplet size and PDI under stress conditions. The optimized system was incorporated into a 1.5% Lesigel^® base to obtain a clear and stable MEG with skin-compatible pH (~ 5.2–5.4) and suitable viscosity (~ 73,500 cP). In vitro permeation studies showed a controlled release profile (96.58 ± 2.80% over 12&#xa0;h) compared with rapid permeation from the marketed formulation Fusiderm^® cream. Kinetic modeling indicated diffusion-controlled release behavior. The FA-MEG exhibited enhanced antibacterial activity against <i>Staphylococcus aureus</i> (41.2 ± 1.4&#xa0;mm) compared with Fusiderm^® cream (36.8 ± 1.2&#xa0;mm), with additional contribution from formulation components. Stability studies confirmed acceptable short-term stability over 3 months under both long-term and accelerated conditions. Overall, the developed FA-MEG represents a nanostructured topical delivery system providing controlled drug release and improved antibacterial performance, offering potential for enhanced management of folliculitis.</p> Graphical Abstract <p></p>