Depression presents risks that are profound and intergenerational, yet research on the association of depression with the physiological processes that might be associated with impaired mental and physical health has only recently been contextualized within the family environment. Participants in this multi-method case–control study were 180 mother-adolescent dyads (50% mothers with a history of depression treatment and current depressive symptoms). In order to examine the association between maternal depression and affective and autonomic reactivity amongst these mothers and their adolescent offspring we collected self-reported measures of positive and negative affect, as well as measures of cardiovascular and electrodermal autonomic activity, during mother-adolescent interaction tasks. Findings indicated that depressed mothers and their adolescent offspring exhibited greater self-reported negative affect reactivity during a problem-solving interaction and blunted (i.e., low) sympathetic activity as measured via skin conductance level across both interaction tasks. These effects remained significant after controlling for a range of potential covariates, including medication use, sex, age, adolescents own mental health symptoms, and behavior of the other interactant, along with correcting for multiple comparisons. Findings indicate that depressed mothers and their adolescent offspring both exhibit patterns of affect and physiology during interactions that are different from those of non-depressed mothers and their offspring, including increased negative affect reactivity during negative interactions and blunted sympathetic activity across both positive and negative interactions. These findings have potential implications for understanding the role of family processes in the intergenerational transmission of risk for depressive disorders.