BackgroundNon-pharmacological approaches for the management of migraine exhibit low to moderate effectiveness due to a lack of high-quality randomized clinical trials. In fact, previous studies applied isolated techniques, which were not representative of common clinical practice. A multimodal approach for migraine may benefit these patients more than isolated approaches. This randomized clinical trial aims to determine the effectiveness of a multimodal protocol combining manual therapy, exercise, and therapeutic pain neuroscience education versus the application of manual therapy or pain neuroscience education alone in patients with migraine.MethodsThis clinical trial will include 75 individuals of both sexes, aged between 18 and 55 years, with migraine. Participants will be randomized into three groups: the therapeutic pain neuroscience education (TPNE; n = 25) group, the manual therapy (MT; n = 25) group, and the multimodal (MM; n = 25) group. The TPNE group will receive one orientation session on migraine and pain self-management, and recommendations for daily active stretching and walking, with subsequent therapist monitoring. The MT group will receive manual therapies targeting musculoskeletal disorders of the cervical spine. The MM group will receive manual therapies targeting musculoskeletal disorders of the cervical spine, active neck exercises, and therapeutic pain neuroscience education. The treatment period will last 12 weeks. The primary outcome will be the headache impact, measured using the Headache Impact Test (HIT-6). Secondary outcomes will include migraine frequency and intensity, cervical mobility and strength parameters, neck pain-related disability, kinesiophobia, cutaneous allodynia, pain-related catastrophizing, quality of life, and self-perception of change. All outcomes will be evaluated at the fourth, eighth, and twelfth weeks of the treatment period. Primary and secondary clinical outcomes, such as headache impact, frequency, and intensity, will also be evaluated at the 1-, 2-, and 4-month follow-ups.DiscussionThe results of this randomized clinical trial may provide high-quality clinical evidence of the effects of non-pharmacological treatment options for the management of migraine.Trial registrationThis study was registered under the access code RBR-7s22c75 in the Registro Brasileiro de Ensaios Clínicos (ReBEC) in December 2020.