The ability of innate immune cells such as macrophages to coordinate a response to danger signals is intimately linked to their metabolic state. Alterations to cellular metabolic pathways such as glycolysis provide the necessary energy, metabolites and changes in gene expression required for inflammatory and anti-microbial responses. Post-translational modifications of metabolic enzymes contribute an important layer of control to these pathways, but our understanding of such mechanisms in the context of innate immunity is currently very limited. Broad-spectrum inhibitors of the eleven classical histone deacetylase (HDAC) enzymes are efficacious in several inflammation-related disease models, and here we reveal that HDACs provide a molecular link between regulated metabolism and innate immune function. We show that a class IIa HDAC inhibitor reprogrammed TLR4-induced metabolic pathways and suppressed inflammatory responses in mouse bone marrow-derived macrophages. Conversely, transgenic mice that overexpress the class IIa enzyme HDAC7 within the myeloid compartment (mac-HDAC7 mice), which we recently generated, displayed exaggerated inflammatory responses both in vitro and following LPS challenge in vivo. Substrates of class IIa HDACs are largely unknown and using an IP/MS approach we identified a novel interaction between HDAC7 and specific glycolytic enzymes, and demonstrate that this interaction regulates the ability of metabolic enzymes to drive inflammatory gene expression. Finally, we reveal that a class IIa HDAC inhibitor protects mice against LPS-induced inflammation in vivo, establishing these enzymes as novel targets for inflammation-related diseases.