Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings. Display omitted •Macrophages adopt a transient metabolic state in response to TLR4 activation•MyD88 and TRIF synergistically facilitate signaling-driven changes in metabolism•Increases in glycolysis and ATP-citrate lyase activity foster histone acetylation•ATP-citrate lyase governs gene induction of a distinct LPS responsive gene set TLR4 activation by LPS induces defined transcriptional cascades. Lauterbach et al. provide evidence that TLR activation induces a transient metabolic state that supports the transcriptional response. Mechanistically, they show that concerted increases in glycolytic flux and ATP-citrate lyase activity foster histone acetylation.