Interictal burden (IB), defined as the symptoms and impairments that occur between migraine attacks, including cognitive dysfunction, photophobia, and fatigue, is recognized as a significant determinant of quality of life in patients. A prospective observational study was conducted. Patients diagnosed with chronic migraine (CM) and under treatment with OnabotulinumtoxinA (OnabotA) according to the PREEMPT protocol (every 12 weeks) were assessed at baseline and at 3, 6, 9, and 12 months. The primary endpoint was to evaluate the change in the IB measured with the Migraine Interictal Burden Scale (MIBS-4) and in the monthly migraine days (MMD). The secondary endpoint was acute medication use. This single-center study included 150 patients (91.3% female; median age 44 years). MIBS-4 scores were decreased by 29.1% at 3 months (8.47 to 5.97) and by 41.6% at 12 months (to 4.86; p < 0.001). IB-free status was achieved by 16 patients (10.7%). The most disabling baseline symptoms were photophobia (37%), fatigue (20%), and allodynia (18%), which reduced by 52%, 43%, and 39% at 12 months, respectively. MMD were reduced from 18.6 to 8.3 days at 12 months and triptan and analgesic intake decreased by 58.7% and 55.4%. OnabotA significantly reduced both IB and migraine frequency over 12 months, underscoring its relevance in CM management.