This study aims to formulate azithromycin oleogel to locally treat skin infections such as acne vulgaris and skin wound infection. Providing a form of azithromycin that can be administered topically is highly desired to prevent unwanted systemic complications including diarrhea, nausea, and abdominal pain. Additionally, it will avoid first pass metabolism, improves patient acceptance, provides an alternative in nauseated patients, decreases the dose by direct contact with the pathological site, and provides a noninvasive and convenient mode of administration. Furthermore, for treating wound infections, the gel will act as a scaffold biomaterial for wound closure besides its antibacterial effect. Herein, we propose the use of grapeseed oil-based oleogel with glycerol monostearate (GMS) as an organogelator as a promising strategy for the effective topical delivery of azithromycin. A series of oleogels were prepared by varying concentrations of organogelators namely GMS, palmitic acid, Compritol 888, and stearic acid, while maintaining the weight ratio of grapeseed oil and clove oil constant. Initial evaluation showed azithromycin oleogel with 15% GMS to be the optimum formulation and it was selected for further evaluation. In vivo testing of the formulated gel showed significant effectiveness in promoting faster clinical healing of Staphylococcus aureus infected wounds. The findings of the present study suggest that azithromycin oleogel is stable, safe, cost-effective, and it provides significant antibacterial activity. © 2022, The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.