Chronic cluster headache (CCH) is an excruciating disorder of unknown pathophysiology, but hypothalamic dysfunction has been implicated. CCH is difficult to treat but on a case-basis, the psychedelic compound psilocybin is said to have beneficial effects. In this first-ever clinical trial (NCT04280055), we evaluate in a small open-label study of CCH patients the feasibility and prophylactic effect of three low-to-moderate doses of psilocybin as well as effects on hypothalamic functional connectivity (FC), using functional magnetic resonance imaging. The treatment was well-tolerated and without serious adverse reactions. Attack frequency was on average reduced by 30% from baseline to follow-up (PFWER=0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with relative reduction in attack frequency, implicating this neural pathway in treatment response. Further clinical studies are warranted to confirm the safety and prophylactic efficacy of psilocybin for CCH and hypothalamic involvement in treatment response.