OnabotulinumtoxinA (BT-A) is one of the few drugs approved for the preventive treatment of chronic migraine (CM). Despite this, some aspects of its mechanism of action are still a matter of debate, and the precise magnitude of BT-A effects needs to be completely elucidated. BT-A acts primarily upon trigeminal and cervical nerve endings, by inhibiting the release of inflammatory mediators such as calcitonin gene-related peptide, as well as reducing the insertion of ionotropic and metabotropic receptors into the neuronal membrane. These actions increase the depolarization threshold of trigeminal and cervical nerve fibers, thus reducing their activation. The central actions of BT-A are still a matter of debate: a retrograde axonal transport has been postulated, but not clearly assessed in humans. Clinically, the efficacy of BT-A in CM has been assessed by large, randomized placebo-controlled trials, such as the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Those results were also confirmed in a wide range of open-label studies, even for long-term periods. Recently, novel findings have led to a better understanding of its pharmacological actions and clinical usefulness in migraine prevention. This narrative review summarizes, updates and critically revises the available data on BT-A and its possible implementation in chronic migraine. Moreover, the current role of BT-A in CM treatment has been discussed.