Intergenerational transmission of internalizing disorders (anxiety and depression) is well documented, but the responsible pathways are underspecified. One possible mechanism is via programming of the child's parasympathetic nervous system (PNS). For example, maternal depression and anxiety, via multiple pathways, may heighten child PNS reactivity, which has been linked to increased risk for internalizing disorders. Heightened PNS reactivity also may sensitize a child to their environment, increasing the vulnerability to developing psychopathology when exposed to stressors, such as maternal psychopathology. In a prospective longitudinal study of mother–child dyads (N = 446), we examined relations among maternal depression and anxiety symptoms when children were infants and aged 3 and 5 years, child respiratory sinus arrythmia (RSA) reactivity (measure of PNS reactivity) at 3 years, and child internalizing symptoms at age 5 years. Consistent with an adaptive calibration perspective, analyses tested the roles of child RSA reactivity as both a mediator and a moderator of associations between maternal and child symptoms. Greater child RSA reactivity in response to a fearful video predicted higher internalizing symptoms among children exposed to higher levels of maternal depression or anxiety symptoms at age 5 years (moderation effects). Child RSA reactivity did not mediate relations between maternal depression or anxiety symptoms in infancy and child internalizing symptoms at age 5 years. The results suggest that heightened PNS reactivity may represent a biological vulnerability to stressful environments early in life: When coupled with maternal depression or anxiety exposure, child PNS reactivity may promote the development of internalizing psychopathology in early childhood.