PURPOSE: The emergence of antimicrobial resistance (AMR) has made treating acne vulgaris increasingly challenging, thus underscoring the urgent need for new antibacterial therapies. This research aimed to discover, for the first time, the efficacy of monensin (MON) against acne pathogens by encapsulating MON in nanostructured lipid carriers (NLCs) to achieve targeted topical delivery. METHODS: MON-loaded NLCs were formulated and optimized using the Design of Experiments (DoE) approach and incorporated in a gel formulation. The potential of MON, MON-NLCs, and its gel formulation was investigated against resistant human isolates of RESULTS: MON-loaded NLCs were developed using stearic acid, oleic acid, and Tween CONCLUSION: This research highlights the novel ability of MON against resistant acne-causing pathogens and the potential of MON-NLCs to deliver MON to the targeted epidermal skin layer effectively.