Ellagic acid (EA) is a natural compound exerting beneficial effects in mammals, including central neuroprotection. Among the central targets, the noradrenergic pathway has been proposed as a suitable candidate and, in this view, we recently proposed the presynaptic α₂ autoreceptors as possible sites of action of this natural polyphenol. Although attractive, our hypothesis is questioned by the unfavourable pharmacokinetic profile of EA, which limits its access to the central nervous system, making impossible its interaction with these receptors. To substantiating the correlation linking EA treatment and the central noradrenergic pathway, we have now extended the study to Urolithins. These are the principal EA metabolites, which are brought in for EA central effects because of their high systemic bioavailability. To address the point, we employed a multidisciplinary approach, which included computational, “in vitro” and “in vivo” studies. The results from “computational” and “in vitro” experiments revealed that Urolithin A (UroA), but not Urolithin B (UroB) or C (UroC), binds to and activates α2 receptor subtypes. Furthermore, the “in vivo” prolonged administration of formulated microdispersion of EA (EAm) in mice led to a marked desensitization of cortical and hippocampal α₂ autoreceptors, also reducing their density. Notably, central effects were associated to a significant changes in gut microbiome composition, towards a metabotype that would preferentially produce UroA. Based on these observations, we propose UroA as one of the systemic “effectors” of the EAm-induced central noradrenergic adaptation, confirming the role of noradrenaline in mediating the EA-mediated health effects.