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<i>Staphylococcus aureus</i> is a commensal bacterium that causes severe infections in soft tissue and the bloodstream. During infection, <i>S. aureus</i> manipulates host cell response to facilitate its own replication and dissemination. Here, we show that <i>S. aureus</i> significantly decreases the level of SUMOylation, an essential post-translational modification, in infected macrophages 24 h post-phagocytosis. The reduced level of SUMOylation correlates with a decrease in the SUMO-conjugating enzyme Ubc9. The over-expression of SUMO proteins in macrophages impaired bacterial intracellular proliferation and the inhibition of SUMOylation with ML-792 increased it. Together, these findings demonstrated for the first time the role of host SUMOylation response toward <i>S. aureus</i> infection.