This study examines the interactive contribution of the hypothalamic-pituitary-adrenal (HPA) axis and approach-avoidance motivation systems to longitudinal changes in depressive symptoms across the adolescent transition. In the summer prior to, or fall of, 4th grade, 132 youth (68 girls; 64 boys; M age = 9.46 years) participated in a social challenge task and reported on their depressive symptoms. In the winter of 6th grade, youth completed a semi-structured interview of depression and a self-report measure of approach-avoidance motivations. Analyses revealed two profiles of risk for adolescent depressive symptoms, with some gender differences: (1) excessive disengagement, reflected in HPA underactivation along with low approach motivation or high avoidance motivation; and (2) excessive engagement, reflected in HPA overactivation along with high approach motivation. This research highlights the importance of a multi-system perspective on development, suggesting that the implications of HPA dysregulation for depressive symptoms are contingent on adolescents’ tendencies toward approach versus avoidance.