Background: This study sought to examine the association between early life stressors and adolescent headache and the potential mediating influence of internalizing psychopathology. Methods: This study used data from 2,313 respondents of the National Longitudinal Survey of Children and Youth, followed prospectively from age 0-1 years at baseline (1994/1995) until age 14-15 years (2008/2009). The relationships between four measures of early life family level stressors, and outcomes of incident health professional diagnosed migraine and self-reported, unclassified frequent headache (>1 per week) were examined using multivariable logistic regression. Mediation analyses of the indirect effect of internalizing psychopathology (i.e., depression and anxiety symptoms) were examined using a regression-based path analytical framework. Results: There were 81 adolescents with incident migraine and 231 with frequent headache. There were no direct associations between early life family level factors and adolescent headache (p > .05). Internalizing psychopathology mediated relationships between family dysfunction (indirect effect [IE] 0.0181, 95% bias-corrected confidence interval [CIBC] 0.0001-0.0570), punitive parenting (IE 0.0241, 95% CIBC 0.0015-0.0633), parental depressive symptomatology (IE 0.0416, 95% CIBC 0.0017-0.0861), and incident migraine, but not frequent headache. Conclusions: Findings provide support for the influence of early life family level factors on prospective risk of developing migraine through internalizing psychopathology.