Neuroinflammation is a pathology common to many neurological diseases, including multiple sclerosis (MS) and stroke. However, therapeutic attempts to modulate neuroinflammation have proved difficult. Neuroinflammatory cells express HCA₂, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA₂ is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation. Furthermore, we discuss the mechanisms underlying the beneficial effects of HCA₂ activation in neuroinflammatory diseases and the therapeutic potential of recently developed synthetic ligands of HCA₂.