Pogostone analogous XW-12 displays an inhibitory effect on Staphylococcus aureus. However, the insolubility of the compound has restricted its further applications. This work aims to improve the water-solubility of XW-12, we used previously synthesised pogostone derivatives XW-12, forming nanoparticles with PLGA-PEG by a single-emulsion solvent-evaporation technique. Characterisations of XW-12 nanoparticles were performed. The in vitro and in vivo experiments confirmed its antimicrobial efficacy and toxicity. The results revealed that the XW-12 NPs had a particle size of approximately 200.0nm, a slower and sustained release. An antibacterial experiment showed that XW-12 NPs had a lower minimal inhibitory concentration value of 1g/mL. In the mouse systemic infection model of MRSA, XW-12 NPs indicated high antibacterial activity. In addition, in vivo, toxicity studies declared that XW-12 NPs had a low cytotoxicity. Therefore, this study suggested that XW-12 NPs may be a great potential antibacterial agent in the treatment of clinical MRSA infection.