In recent years, multidrug-resistant bacteria have developed the ability to resist multiple antibiotics, limiting the available options for effective treatment. Raising awareness and providing education on the appropriate use of antibiotics, as well as improving infection control measures in healthcare facilities, are crucial steps to address the healthcare crisis. Further, innovative approaches must be adopted to develop novel drug delivery systems using polymeric matrices as carriers and support to efficiently combat such multidrug-resistant bacteria and thus promote wound healing. In this context, the current work describes the use of two biocompatible and non-toxic polymers, poly(vinyl alcohol) (PVA) and xanthan gum (XG), to achieve hydrogel networks through cross-linking by oxalic acid following the freezing/thawing procedure. PVA/XG-80/20 hydrogels were loaded with different quantities of neomycin sulfate to create promising low-class topical antibacterial formulations with enhanced antimicrobial effects. The inclusion of neomycin sulfate in the hydrogels is intended to impart them with powerful antimicrobial properties, thereby facilitating the development of exceptionally efficient topical antibacterial formulations. Thus, incorporating higher quantities of neomycin sulfate in the PVA/XG-80/20-2 and PVA/XG-80/20-3 formulations yielded promising cycling characteristics. These formulations exhibited outstanding removal efficiency, exceeding 80% even after five cycles, indicating remarkable and consistent adsorption performance with repeated use. Furthermore, both PVA/XG-80/20-2 and PVA/XG-80/20-3 formulations outperformed the drug-free sample, PVA/XG-80/20, demonstrating a significant enhancement in maximum compressive stress.