We previously showed that the class IIa histone deacetylase (HDAC), HDAC7 drives production of key Toll-like receptor inducible inflammatory mediators, such as Il-1β and Ccl2, as well as systemic inflammation after lipopolysaccharide (LPS) challenge. It may therefore be a potential target for intervention in inflammation-linked diseases, thus necessitating assessment of its involvement in infectious disease processes. Here we report that, in a uropathogenic E. coli intraperitoneal challenge model, both pharmacological inhibition of class IIa HDACs with TMP195 and myeloid knockout of Hdac7 increased bacterial loads in the liver and spleen. Systemic inflammation was also exacerbated, as evidenced by increased core body temperature and elevated sera levels of specific inflammatory mediators. Similarly, inhibition of class IIa HDACs with TMP195 in murine bone marrow-derived macrophages (BMM) and human macrophage-like PMA-differentiated THP-1 cells impaired their capacity to kill both non-pathogenic and uropathogenic E. coli. These data demonstrate that myeloid Hdac7 is required for effective host defence against bacterial infection. We previously reported that Hdac7 promotes glycolysis-associated inflammatory mediators, which is licensed by deacetylation of the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) at lysine 433. However, the antimicrobial effect of Hdac7 in murine macrophage is independent of Pkm2, as overexpression of wild type and deacetylation mimics of Pkm2 in BMM not alter macrophage antibacterial responses. Instead, we show that Hdac7 is required for effective phagocytosis in macrophages. Furthermore, LPS-inducible Ccl2 production requires both Hdac7 enzyme activity and Pkm2, but occurs independently of Pkm2 deacetylation at K433. These findings thus demonstrate that Hdac7 acts through multiple mechanisms to drive both antimicrobial and inflammatory pathways in macrophages.