The objective of the study was to develop a topical foam formulation of mupirocin for the prevention and treatment of skin wounds, especially burn wounds. The pre-foam formulation was prepared by mixing oil and aqueous phase containing 2% mupirocin at 70 °C. This system was filled in the canister and crimped with aerosol propellant grade LPG to achieve pressurized foam. The foam formulation was statistically optimized by Box-Behnken design to check the effect of gelling agent (HPC), surfactant concentration (crodesta F110) and foaming adjuvants (oleyl and stearyl alcohol) on critical foam characteristics. These independent variables showed a significant effect on collapse time and foam density. The optimized formulation was evaluated for physicochemical properties, in vitro release and antibacterial activity. The optimum batch showed a collapse time of 85 s and had excellent spreadability. The diffusion study showed that more than 90% of the drug was released within 6 h. The formulation exhibited an antimicrobial effect against S. aureus which was 0.75-fold better than the marketed preparation of mupirocin. The foam-formulation has the unique nature of collapsing upon slight tap which is highly beneficial for application with medical gauze. Therefore, mupirocin foam formulation with quick collapse time, good spreadability and superior antibacterial efficacy can be explored for burn wounds with a minimum touch.