Patients with migraine suffer from high morbidity related to the repeated headache attacks, characteristic of the disorder, poor sleep, and a high prevalence of comorbid psychosocial disorders. Current pharmacological therapies do not address these aspects of migraine, but nonpharmacological treatments such as mindfulness-based stress reduction (MBSR) have been shown to improve both pain and psychological well-being. In this secondary analysis, we examined the change over time in sleep quality and psychosocial outcomes from the magnetic resonance imaging outcomes for mindfulness meditation clinical trial and assessed how these mediated treatment response (50% reduction in headache frequency postintervention). We also examined the relationship between baseline values and treatment response. The trial (primary outcomes previously reported) included 98 patients with episodic migraine randomized to either enhanced MBSR (MBSR+) or stress management for headache. They completed psychosocial questionnaires and headache diaries at baseline (preintervention), midintervention (10 weeks after baseline), and postintervention (20 weeks after baseline). There was a significant improvement in sleep quality from baseline to postintervention (P = 0.0025) in both groups. There were no significant changes from baseline or between groups in anxiety, depression, and stress. There was also no significant association between baseline scores and treatment response. Mediation analysis showed a significant indirect effect of 6% for sleep: In other words, small improvements in sleep may have contributed to the efficacy of MBSR+.Trial registration: NCT02133209.