Significance GHB is a natural brain metabolite of GABA, previously reported to be neuroprotective. However, the high-affinity binding site for GHB has remained elusive for almost 40 y. We here unveil CaMKIIα, a highly important neuronal kinase, as the long-sought-after GHB high-affinity target. Via a specific interaction within the central hub domain of CaMKIIα, GHB analogs act to stabilize the hub oligomer complex. This interaction potentially explains pronounced neuroprotective effects of GHB analogs in cultured neurons exposed to a chemical insult and in mice exposed to ischemia. The postischemic treatment effects of GHB analogs underline these compounds as selective and high-affinity potential drug candidates and CaMKIIα as a relevant pharmacological target for stroke therapy.