Methicillin-resistant Staphylococcus aureus (MRSA) is a significant concern for skin and soft tissue infections. Apart from biofilm formation, these bacteria can reside intracellularly in phagocytic and nonphagocytic mammalian cells, complicating treatment with conventional antibiotics. Lipid-polymer hybrid nanoparticle (LPN) systems, combining the advantages of polymeric nanoparticles and liposomes, represent a new generation of nanocarriers with the potential to address these therapeutic challenges. In this study, gentamicin (Gen) and vancomycin (Van) were encapsulated in LPNs and evaluated for their ability to eliminate intracellular MRSA in phagocytic macrophage RAW-Blue cells and nonphagocytic epithelial HaCaT cells. Compared to free antibiotics at 100 μg/mL, LPN formulations significantly reduced intracellular bacterial loads in both cell lines. Specifically, LPN-Van resulted in approximately 0.7 Log CFU/well reduction in RAW-Blue cells and 0.3 Log CFU/well reduction in HaCaT cells. LPN-Gen showed a more pronounced reduction, with approximately 1.26 Log CFU/well reduction in RAW-Blue cells and 0.45 Log CFU/well reduction in HaCaT cells. In vivo, LPN-Van at 500 μg/mL significantly reduced MRSA biofilm viability compared to untreated controls (p < 0.001), achieving 98% eradication based on median values. In comparison, free vancomycin achieved a nonstatistically significant 79.2% reduction in biofilm viability compared to control. Prophylactically, LPN-Van at 500 μg/mL decreased MRSA levels to the limit of detection, resulting in a ∼3.5 Log reduction in the median CFU/wound compared to free vancomycin. No acute dermal toxicity was observed for LPN-Van based on histological analysis. These data indicate that LPNs show promise as a drug delivery platform technology to address intracellular infections.