It remains unclear how the COVID-19 pandemic has affected the mother–infant relationship and associations between maternal postpartum depression (PPD) and offspring temperament. This study examined the impact of the pandemic on these links and how maternal ratings of the mother–infant relationship mediated associations between PPD and infant temperament in a sample of treatment-seeking mothers in Ontario, Canada before and during the COVID-19 pandemic. Mothers with infants <12 months of age and Edinburgh Postnatal Depression Scale scores ≥10 enrolled in two separate randomized controlled trials of 1-day cognitive behavioral therapy-based workshops for PPD conducted before COVID-19 (n = 392) and during the pandemic (n = 403). Mothers reported on depressive symptomatology, infant temperament, and the mother–infant relationship. Maternal PPD was associated with more infant negative affectivity and mother–infant relationship difficulties. While associations between PPD and infant-focused anxiety were stronger during COVID-19, the pandemic did not otherwise affect associations between PPD and infant temperament. Mediation analyses suggested that aspects of the mother-infant relationship mediated associations between PPD and infant negative affectivity. Findings highlight the importance of detecting PPD and intervening to potentially improve outcomes for mothers and their children.