--- - |2+ Background Exposure to maternal depression bears long‐term negative consequences for children's well‐being. Yet, no study has tested the joint contribution of maternal and child's hypothalamic pituitary axis and immune systems in mediating the effects of maternal depression on child psychopathology. Methods We followed a birth cohort over‐represented for maternal depression from birth to 10 years (N = 125). At 10 years, mother and child's cortisol (CT) and secretory immunoglobulin A (s‐IgA), biomarkers of the stress and immune systems, were assayed, mother–child interaction observed, mothers and children underwent psychiatric diagnosis, and children's externalizing and internalizing symptoms reported. Results Depressed mothers had higher CT and s‐IgA levels and displayed more negative parenting, characterized by negative affect, intrusion, and criticism. Children of depressed mothers exhibited more Axis‐I disorders, higher s‐IgA levels, and greater social withdrawal. Structural equation modeling charted four paths by which maternal depression impacted child externalizing and internalizing symptoms: (a) increasing maternal CT, which linked with higher child CT and behavior problems; (b) augmenting maternal and child's immune response, which were associated with child symptoms; (c) enhancing negative parenting that predicted child social withdrawal and symptoms; and (d), via a combined endocrine‐immune pathway suppressing symptom formation. Conclusions Our findings, the first to test stress and immune biomarkers in depressed mothers and their children in relation to social behavior, describe mechanisms of endocrine synchrony in shaping children's stress response and immunity, advocate the need to follow the long‐term effects of maternal depression on children's health throughout life, and highlight maternal depression as an important public health concern. - Depression and Anxiety, EarlyView.