The Cannabidiol (CBD) are extensively used owing to their potent antibacterial effects. We developed CBD-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles using an emulsion process technology, resulting informing the PLGA@CBD nanoparticles. The emulsion parameters were optimized using three-dimensional surface plots. When scaled up under optimal conditions, the corresponding loading content efficiency were 16.51%. Compared with natural cannabidiol, the physically modified PLGA nanoparticles became smooth, round, and solid, improving their water solubility and bioavailability, realizing long-time antibacterial. Therefore, the nanoparticles showed better efficacy against Gram-positive bacteria. Our results confirm that the PLGA@CBD nanoparticles have been achieved as long-acting antibacterial delivery system, which improved the treatment efficiency.