BACKGROUND: Our aim was to describe the relationship between risk factors, such as stress, depression, and anxiety, and potentially protective factors against pediatric headache-related disability, such as mindfulness, resilience, and self-compassion, and to determine teens' interest in mind-body skills training to help reduce headache-related disability. METHODS: This was a cross-sectional survey among adolescents seen in an academic neurology clinic reporting four or more headaches monthly using standardized instruments to determine the relationship between putative risk and protective factors as well as physiologic markers of inflammation and vagal tone and headache-related disability. RESULTS: Among the 29 participants, 31% were male, the average age was 14.8 years, average headache frequency was 11.6 per month, and the most commonly reported trigger was stress (86%). The only risk or protective factor significantly associated with headache-related disability was depression (r = 0.52, P = 0.004). Depression was negatively correlated with mindfulness, resilience, and self-compassion (P < 0.01 each) and positively correlated with stress, sleep disturbance, and anxiety (P < 0.01 each). Biomarkers of vagal tone and inflammation were correlated with each other but not with headache-related disability or depression. There was strong interest in learning skills like slow, deep breathing practices supported by a smart phone application to reduce stress and the negative impact of headaches on daily life. DISCUSSION: Among teens with frequent migraine headaches, depression is the strongest risk factor for headache-related disability. Stress is viewed as a headache trigger, and teens reported wanting to learn simple stress management strategies supported by a smart phone application to help reduce headache-related disability.