Toll-like receptors (TLRs) reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid (TCA) cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulate both TLR-inducible glycolysis and inflammatory responses. Here, we report that the TLR4 agonist lipopolysaccharide (LPS) rapidly increases enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this lysine deacetylase during macrophage activation. Except for the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate (ECAR), was attenuated in Hdac7-deficient mouse macrophages responding to sub-maximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1b and Ccl2. Thus, LPS triggers MyD88-dependent activation of Hdac7 enzymatic activity in macrophages, with this being required for inducible production of specific inflammatory mediators, such as Il-1b and Ccl2. Additionally, Hdac7 is essential for instructing the acute glycolysis response in macrophages responding to sub-maximal concentrations of LPS, via a mechanism that does not require its enzymatic activity. Hdac7 is thus a bifurcation point for regulated metabolism and cytokine responses in macrophages responding to low dose LPS. We propose that this lysine deacetylase may be particularly important during chronic low-grade inflammation. Consistent with this, we find that HDAC7 expression is elevated in liver biopsies from patients with late-stage chronic liver disease. Collectively, our study shows that HDAC7 has key roles in both TLR-inducible metabolic reprogramming and inflammatory responses in macrophages, likely through distinct molecular mechanisms.