The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders.