INTRODUCTION: Liposomal hydrogels are novel drug delivery systems that comprise preformed liposomes incorporated in hydrogels destined for mostly localized drug therapy, herewith antimicrobial therapy. The formulation benefits from versatility of liposomes as lipid-based nanocarriers that enable delivery of various antimicrobials of different lipophilicities, and secondary vehicle, hydrogel, that assures better retention time of formulation at the infection site. Especially in an era of alarming antimicrobial resistance, efficient localized antimicrobial therapy that avoids systemic exposure of antimicrobial and related side effects is crucial. AREAS COVERED: We provide an overview of liposomal hydrogels that were developed for superior delivery of antimicrobials at different infections sites, with focus on skin and vaginal infections. The review summarizes the challenges of infection site and most common infection-causing pathogens and offers commentary on most relevant features the formulation needs to optimize to increase the therapy outcome. We discuss the impact of liposomal composition, size, and choice of polymer-forming hydrogel on antimicrobial outcome based on the literature overview and own experience in the field. EXPERT OPINION: Liposomal hydrogels offer improved therapy outcome in localized antimicrobial therapy. By fine-tuning of liposomal as well as hydrogel properties, formulations with superior performance can be optimized targeting specific infection site.