Introduction Acute medication overuse is prevalent in patients with migraine. Methods In three phase 3, double-blind, randomized, placebo-controlled studies, patients with episodic migraine (EVOLVE-1 and EVOLVE-2) or chronic migraine (REGAIN) were randomized 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg for 3 or 6 months. This subgroup analysis evaluated mean changes in the number of monthly migraine headache days in each treatment among patients with versus without baseline acute medication overuse via mixing modelling with repeated measures. Results The percentages of patients with baseline medication overuse in placebo, galcanezumab 120-mg and 240-mg groups, respectively, were 19.4%, 17.3%, and 19.3% for EVOLVE-1/-2 (pooled; post hoc), and 63.4%, 64.3%, and 64.1% for REGAIN ( a priori). Both galcanezumab doses demonstrated significant improvement compared with placebo for overall least squares mean change in monthly migraine headache days in patients with baseline medication overuse in both the episodic and chronic migraine studies ( p ≤ 0.001). Furthermore, both galcanezumab doses reduced average monthly medication overuse rates compared to placebo ( p < 0.001) in both patient populations with medication overuse at baseline. Conclusions Galcanezumab appears to be effective for the preventive treatment of episodic and chronic migraine in patients who overuse acute medications. Trial registration: ClinicalTrials.gov Identifiers: NCT02614183, NCT02614196, and NCT02614261