Aim: To elucidate the effect of chrysin on a-haemolysin production by Staphylococcus aureus and protection against pneumonia in a murine model. Methods and Results: Haemolysis, Western blot and real-time RT-PCR assays were performed to evaluate the effect of chrysin on alpha-haemolysin secretion by Staph. aureus. The efficacy of chrysin against human alveolar epithelial cell injury by alpha-haemolysin was tested using live/dead staining or by measuring lactate dehydrogenase activity. Furthermore, we determined the protective effect of chrysin against Staph. aureus pneumonia through histopathology experiments in a mouse model. The production of alpha-haemolysin by Staph. aureus was inhibited when presented with an increasing subinhibitory concentration of chrysin in vitro. Consistent with this result, chrysin prevented alpha-haemolysin-mediated cell injury and protected mice from Staph. aureus pneumonia. Conclusions: Chrysin is a potent inhibitor of alpha-haemolysin expression by Staph. aureus, and it conferred a significant degree of protection against Staph. aureus pneumonia. Significance and Impact of Study: The chrysin-mediated inhibition of alpha-haemolysin production and protection against Staph. aureus pneumonia may offer a new strategy in combating pathogen infections.