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Abstract Although autophagy and phagocytosis are involved in the regulation of host inflammatory response to bacterial infection in macrophages, the underlying mechanisms have not been completely elucidated. In the present study, we found that infecting RAW264.7 macrophages with Staphylococcus aureus (S. aureus) activated multiple signaling pathways including phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt), nuclear factor-κB (NF-κB), and Rac1, as well as triggered autophagy. LY294002, a specific PI3K activity inhibitor, significantly decreased autophagy and phagocytosis of macrophages upon S. aureus infection. Similarly, knockdown of Beclin1 by specific siRNA significantly inhibited autophagy and phagocytosis of S. aureus -infected macrophages. Additionally, we showed that although administration of Beclin1 siRNA had no effects on phosphorylation of Akt (p-Akt), inhibition of PI3K activity by LY294002 significantly decreased the expression of Beclin1, suggesting that Beclin1 is a downstream molecular of PI3K. Furthermore, inhibition of autophagy significantly increased the production of NF-κB-dependent TNFα/IL-1β in S. aureus -infected macrophages. Collectively, these findings demonstrated, for the first time, that the PI3K/Akt-Beclin1 signaling pathway positively regulates phagocytosis and negatively mediates NF-κB-dependent inflammation in S. aureus -infected macrophages. Highlights • S. aureus activates multiple signaling pathways and triggers autophagy in RAW264.7 cells. • Inhibition of PI3K activity decreases autophagy and phagocytosis of S. aureus -infected RAW264.7 cells. • Knockdown of Beclin1 reduces the phagocytosis of S. aureus -infected RAW264.7 cells. • Inhibition of autophagy increases the production of NF-κB dependent TNF-α/IL-1β in S. aureus -infected RAW264.7 cells. [ABSTRACT FROM AUTHOR]