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Mother-infant interactions are co-regulated and provide the foundation for mother-infant relationship quality. The implications of maternal depression and contextual demands (i.e., reinstating the interaction following maternal unavailability and vocalized infant distress) on observationally coded co-regulation in mother-infant dyads (n = 40) at 4-months was investigated. Associations among co-regulation patterns and mother-infant relationship quality was also examined. Dyads participated in Still-Face (SF) and Separation (SP) procedures, with periods of maternal emotional and physical unavailability. Co-regulation was captured using the Revised Relational Coding System. Relationship quality was examined using the Emotional Availability Scales. Dyads in the depressed group had significantly more unilateral exchanges than the non-depressed group following the SF and SP perturbations. The depressed group also had significantly more distress vocalizations during the SP perturbation than the non-depressed group. Co-regulation in the depressed group was less disrupted by the SF perturbation. Positive relationship quality dimensions (maternal sensitivity, structuring, and infant responsiveness) were associated with more symmetrical and less unilateral co-regulation regardless of the interaction period. There were also context-specific results pertaining to patterns of co-regulation and associated maternal hostility and infant responsiveness. Results highlight co-regulatory differences in depressed mothers and their infants and how these differences are exacerbated by contextual demands.