Serum Amyloid A (SAA) proteins are acute-phase reactants with critical roles in sterile and bacterial inflammation. Through and experiments, we demonstrate that SAA proteins amplify cytokine and chemokine responses during sterile inflammation and enhance bacterial clearance in infectious conditions. Mechanistically, SAA proteins augment NF-κB signaling, driving pro and anti-inflammatory mediator production. mice carrying a deletion of the , , , and serum amyloid A genes have better survival rates in sterile sepsis but are more prone to bacterial sepsis than their counterparts, emphasizing their dual functionality in immune regulation. Overexpression of , , , and in macrophages enhances NF-κB-mediated pro-inflammatory cytokine production and bacterial clearance during infection. Together, our results show that SAA proteins are key modulators of inflammation, with distinct mechanisms tailored to sterile and infectious contexts.