INTRODUCTION: Migraine is recognized as a complex neurological disorder that has imposed a social burden. We assessed the signaling pathways and molecular mechanisms based on the in silico analysis and predicted drug candidates by the biomedicine approach. Moreover, we evaluated high-intensity interval training and vitamin B12 + magnesium on women's migraine attacks and inflammatory status. METHODS: This study computed differential gene expression in migraine syndrome and the dimension network parameters visualized by software. Moreover, we proposed the functional mechanism and binding energy of essential micronutrients on macromolecules based on drug discovery. In this clinical trial, 60 cases were randomized to four groups, including applied high-intensity interval training (HIIT), cases consumed supplementation vitamin B12 and magnesium (Supp), cases applied high-intensity interval training, and consumed supplementation (HIIT + Supp), and migraine cases for 2 months. Serum levels of calcitonin gene-related peptide (CGRP) were measured at baseline and at the end of the study. In addition, migraine disability assessment score (MIDAS), frequency, intensity, and duration were recorded before and during interventions. RESULTS: In silico study revealed the association between inflammation signaling pathways and pathogenesis of migraine attacks as a remarkable pathomechanism in this disorder. Furthermore, serum concentrations of CGRP were significantly declined in the HIIT + Supp compared with other groups. In addition, MIDAS, frequency, intensity, and duration were reduced in the HIIT + Supp group compared with the other groups. CONCLUSION: We found that the synergistic effects of cobalamin and magnesium followed by regular exercise could silence the inflammation signaling pathway, and a combination of HIIT + Supp could ameliorate migraine pain. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials; IRCT code: IRCT20170510033909N12. Approval Data: 2021/06/02.