Background Family environment plays an important role in the intergenerational transmission of major depressive disorder (MDD), but less is known about how day‐to‐day mother–child interactions may be disrupted in families with a history of MDD. Disruptions in mother–child synchrony, the dynamic and convergent exchange of physiological and behavioral cues during interactions, may be one important risk factor. Although maternal MDD is associated with a lack of mother–child synchrony at the behavioral level, no studies have examined the impact of maternal MDD on physiological synchrony. Therefore, this study examined whether maternal history of MDD moderates mother–child physiological synchrony [measured via respiratory sinus arrhythmia (RSA)] during positive and negative discussions. Method Children aged 7–11 years and mothers with either a history of MDD during the child's lifetime (n = 44) or no lifetime diagnosis of any mood disorder (n = 50) completed positive and negative discussion tasks while RSA was continuously recorded for both child and mother. Results Results indicated significant between‐dyad and within‐dyad group differences in physiological synchrony during positive and negative discussions. Between‐dyad analyses revealed evidence of synchrony only among never depressed dyads, among whom higher average mother RSA during both discussions was associated with higher average child RSA. Within‐dyad analyses revealed that never depressed dyads displayed positive synchrony (RSA concordance), whereas dyads with a history of maternal MDD displayed negative synchrony (RSA discordance) during the negative discussion and that the degree of negative synchrony exhibited during the negative discussion was associated with mothers' and children's levels of sadness. Conclusions These results provide preliminary evidence that physiological synchrony is disrupted in families with a history of maternal MDD and may be a potential risk factor for the intergenerational transmission of depression.