The histamine H₃ receptor mediates inhibitory responses in the nervous system. Here, we demonstrate the coupling of the human histamine H₃ receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus oocytes, using voltage-clamp. The histamine H₃ receptor agonist (R)-α-methylhistamine increased GIRK currents with an EC₅₀ of 2.5 nM. The response to (R)-α-methylhistamine was inhibited by the specific antagonist/inverse agonist clobenpropit. GIRK channels represent a novel effector pathway for the histamine H₃ receptor, also suggesting the use of electrophysiology assays in histamine H₃ receptor drug screening, allowing for the resolution of G protein activation kinetics.