Given high health costs of depression during pregnancy and the first postnatal year, it is important to understand mechanisms involved in the emergence and perpetuation of symptoms during this time. In a series of 2 studies, we aim to clarify bidirectional relations between mothers’ physiological stress regulation—stress-related activation of the hypothalamic-pituitary-adrenal (HPA) axis—and their course of depressive symptoms. In Study 1, 230 pregnant women recruited from a women’s mental health program gave 3 saliva samples in the context of psychosocial stress at 24, 30, and 36-weeks gestation. They self-reported depressive symptoms across the three trimesters of pregnancy and first year postpartum. Multilevel models revealed women with elevated salivary cortisol during pregnancy showed a course of escalating ante- and postnatal symptoms, implicating HPA hyperactivation as a precursor to worsening mood problems. In Study 2, 54 mothers from a community sample self-reported depressive symptoms at 3, 6, 12, and 18 months postnatal. At 18 months, they participated in a dyadic stress task with their infant and gave 4 saliva samples for cortisol assay. For mothers with a lifetime depression diagnosis, an escalating course of postnatal symptoms predicted a higher, flatter cortisol response profile. Together, the results of these studies suggest that for high-risk mothers, a trajectory of worsening depression may both follow from and give rise to neuroendocrine stress hyperactivation. These findings suggest greater attention is warranted to course of depressive symptoms across the ante- and postnatal period, rather than symptom levels at any given time, to characterize health risks.