Abstract Introduction Many patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mG lu 5 receptor. Methods We studied the effect of mG lu 5 blockade using ADX 10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mG lu 5 mechanism was tested with ADX 10059 orally in a double‐blind placebo‐controlled, parallel group, clinical trial. Results The negative allosteric mG lu 5 modulator ADX 10059 attenuated dural vasodilator responses to meningeal stimulation in a dose‐dependent manner, comparable to naratriptan, while the N ‐methyl‐ d ‐aspartate receptor blocker MK ‐801 had no effect. ADX 10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mG lu 5 and not mG lu 1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX 10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment‐emergent event at 48%. Interpretation Our findings provide preclinical and clinical proof of concept establishing mG lu 5 as a novel therapeutic target in the treatment of migraine. Although ADX 10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.