α-Cyperone, that is isolated from the rhizomes of Cyperus rotundus L, significantly inhibited PGE2 production by suppressing the LPS-induced expression of inducible COX-2 at both the mRNA and the protein levels. In contrast, α-cyperone had little effect on NO production and iNOS expression. Additionally, α-cyperone downregulated the production and mRNA expression of the inflammatory cytokine IL-6. Moreover, treatment with α-cyperone suppressed the transcriptional activity of NFκB and the nuclear translocation of the p65 NFκB subunit in LPS-induced RAW 264.7 cells. Alpha-Cyperone also significantly decreased the adherence of APEC-O78 to chicken type II pneumocytes. In addition, alpha-Cyperone inhibited actin cytoskeleton polymerization induced by APEC-O78 through down regulating the expression of Nck-2, Cdc42 and Rac1. Besides, Alpha-Cyperone is a promising inhibitor of Hla production by S. aureus and protects lung cells from this bacterium. Thus, alpha-Cyperone may provide the basis for a new strategy to combat S. aureus pneumonia.