Azithromycin (AZ) is an azalide macrolide antibiotic that is frequently employed for treating bacterial skin infections. It suffers from limited oral bioavailability, which results from incomplete absorption or extensive first-pass metabolism. Therefore, preparing azithromycin formulations for topical administration is highly recommended to avoid first-pass metabolism and to boost the concentration of the drug on the skin. The objective of our investigation was to formulate and evaluate the efficacy of AZ-loaded nanoemulgel as an antimicrobial drug. The physical appearance, spreadability, viscosity, particle size, in vitro drug release, ex vivo permeation investigations, and antimicrobial efficiency of the prepared formulations were evaluated. The prepared formulation loaded with AZ exhibited good physical quality. AZ-loaded nanoemulgel had a greater ex vivo drug permeation across rabbit skin than other formulations (AZ-loaded gel and AZ-loaded emulgel), revealing improved drug permeation and greater transdermal flux in addition to enhanced antibacterial efficacy (p < 0.05). Overall, our findings imply that tea-tree-oil-based nanoemulgel would be a promising delivery system for enhancing the antimicrobial efficiency of azithromycin.