Methicillin-resistant Staphylococcus aureus (MRSA) is a well-recognized cause of bacterial pneumonia, resulting in increased morbidity and mortality worldwide. However, the rediscovery of antibacterial compounds that belong to established antibiotics classes remains a bottleneck, and also has the risk of superbugs emergence and microbiomes imbalance. A potential advantage by using non-antibiotics is that there is no “life or death” selection pressure on bacteria, so they are less likely to evolve resistance. Here, the Chinese herbal compound celastrol (CST), a triterpene methylene quinone was used to synthesize a chitosan-coated self-assembled celastrol nanoparticles (CSC NPs) for Staphylococcus aureus (SA) and clinical isolated MRSA pneumonia treatment by nebulization with an aerodynamic size of 3 µm to allow predominant deposition in the deep lung. The CSC NPs exhibited high drug loading efficiency via hydrophobic interaction and demonstrated enhanced mucoadhesive properties through electrostatic interactions with the mucus layer, leading to prolonged pulmonary retention. This was followed by acid-responsive degradation at bacterial infection sites, facilitating mucus penetration. Further mechanistic analysis demonstrated that CSC NPs as a non-competitive inhibitor of dehydrosqualene synthase (CrtM), caused reduction of staphyloxanthin (STX) that is a significantly important virulence factor in S. aureus, so that disrupting the bacterial membrane and enhancing immune clearance by host macrophages and neutrophils. Therefore, CSC NPs exhibited excellent antibacterial activity against MRSA with minimum inhibitory concentrations (MICs) of 8 μg/mL. In a mouse model of SA and MRSA pneumonia, CSC NPs effectively reduced bacterial burden for substantially enhanced the therapeutic effects (the antibacterial rate was 97% and 94%, respectively). Overall, our study provides a new alternative strategy by using conventional natural products to overcome SA and MRSA infections with great prospects for clinical translation.