Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.