Staphylococcus aureus (S. aureus), particularly methicillin-resistant strains (MRSA), poses a significant threat to global public health due to its resistance to conventional antibiotics. The urgent need for alternative treatments has highlighted cepharanthine (CEP), a bisbenzylisoquinoline alkaloid, known for its antiviral, antibacterial, and anti-inflammatory properties. However, the clinical application of CEP is constrained by several factors. These include the requirement for a high therapeutic dosage, low aqueous solubility, restricted oral absorption, and a short half - life. In this study, we developed a chitosan-coated Poly Lactic-co-Glycolic Acid (PLGA) nanoemulsion encapsulating CEP (CCPN) using the double-emulsion solvent evaporation method. The formulation was optimized to achieve ideal physicochemical properties, including a particle size of 588.13 ± 31.87 nm and a zeta potential of 48.60 ± 1.00 mV, ensuring stability and uniformity. Biological evaluations demonstrated that CCPN effectively inhibited hemolysis, suppressed biofilm formation, disrupted mature biofilms, and displayed potent antibacterial activity against S. aureus. In vivo studies using a murine pneumonia model revealed that CCPN significantly alleviated lung damage, reduced bacterial load, mitigated inflammatory responses, and improved survival rates of mice infected with S. aureus or MRSA. These findings highlight CCPN as a promising therapeutic strategy for treating bacterial pneumonia. This novel nanoemulsion effectively tackles the key limitations in antimicrobial therapy by boosting the solubility, stability, and antibacterial efficacy of CEP. It holds great promise in the fight against antibiotic - resistant infections and shows substantial potential for promoting the treatment of pulmonary diseases.