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Abstract Introduction The introduction of clacitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has revolutionized the treatment of migraines. In clinical practice gepants might be considered as a valid option to treat acute attacks in patients with migraine who are treated with mAbs. However, the safety and tolerability of such a combination is not well addressed in the real-world setting. We designed this study to evaluate the safety and tolerability of combining CGRP mAbs with gepants in the management of migraines. Methods This was a retrospective, real-world, exploratory study. The participants included within the study were adult (≥ 18 years) patients diagnosed with migraine. Screening for patients who were treated with at least one GCRP mAbs was done. Data was collected from one site, the American Center for Psychiatry and Neurology, Abu Dhabi UAE. A total of 516 patients taking CGRP mAbs were identified. Extracted data from patients’ electronic medical records included patient demographics, migraine characteristics, prescribed treatments, and adverse events (AEs). The tolerability and safety of the combination therapy was evaluated on the basis of documented AEs. Results Among the identified 516 patients, 234 were administered gepants in addition to the CRGP mAb (215, rimegepant; 19, ubrogepant). Eleven of the 234 patients switched from rimegepant to urogepant as a result of lack of efficacy; one patient switched from urogepant to zolmitriptan because of the lack of insurance coverage of the former medication. Among all the patients included in this study, three AEs were documented. These AEs were generally mild and transient and hence did not lead to discontinuation of treatment. Moreover, 42 of the 234 (17.9%) patients were switched from one class of CGRP mAbs to another at least once while continuing treatment with the assigned gepants. Conclusion The findings of this study demonstrate that combining CGRP mAbs with gepants is a safe and well-tolerated treatment approach for migraine. Future studies are warranted to further validate these findings and explore long-term outcomes.