Histone deacetylases (HDACs) remove acetyl groups from lysine residues of histone and non-histone proteins. Class IIa HDACs (HDAC4, 5, 7, 9) drive macrophage inflammatory responses, but their contributions to host defence have not been explored. Here, we show that pharmacological or genetic targeting of Hdac7 led to greatly increased bacterial loads and dissemination of a representative strain (EC958) of the globally-disseminated and multidrug-resistant uropathogenic Escherichia coli clone ST131 in an intraperitoneal challenge model in mice. Challenge of primary mouse macrophages with E. coli also resulted in a rapid increase in class IIa HDAC enzyme activity. Pharmacological or genetic targeting of Hdac7 impaired phagocytosis of E. coli and bacterial clearance by primary murine macrophages. Conversely, primary macrophages from Mac-Hdac7 mice that selectively over-express Hdac7 in myeloid cells displayed increased phagocytosis and intracellular killing in comparison to control cells. In response to E. coli infection, Hdac7-deficient macrophages exhibited an impaired metabolic shunt towards the pentose phosphate pathway that is required for reactive oxygen species (ROS) production. Consistent with this, Hdac7 was also required for phagocyte oxidase-dependent reactive oxygen species production, with inhibition of either glucose uptake or phagocyte oxidase activity blocking the antimicrobial phenotype of Mac-Hdac7 macrophages. Mechanistically, we provide evidence that Hdac7 drives antimicrobial responses via the pentose phosphate pathway enzyme, 6-phosphogluconate dehydrogenase (6-PGD). Genetic targeting or pharmacological inhibition of Hdac7 significantly reduced the activity of 6-PGD, an enzyme generating NADPH for phagocyte oxidase function. Finally, in contrast to its role in promoting lipopolysaccharide (LPS)-driven IL-1b production, Hdac7 actually limits E. coli-induced IL-1b secretion, suggesting that this class IIa HDAC discriminates between different types of danger. We propose that HDAC7 responds to local threats by coordinating effective innate defence and limiting leukocyte recruitment, whereas it drives a systemic inflammatory response upon sensing distal danger.