Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid β-protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β-adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ-induced inflammation as did mice in EE. Conversely, mice in EE fed the β-adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2-adrenergic receptors showed no protection of microglia by EE. In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial-specific analysis of β2-adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE. Thus, enhanced β-adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers in vivo.