The COVID-19 pandemic is an unanticipated and uncontrollable chronic stressor that is detrimental to the mental and behavioral health of children and families, particularly those from disadvantaged and marginalized backgrounds. Chronic stress impairs a myriad of prefrontal cortical functions, important for coping with the COVID-19 pandemic, and has consequences on dyadic parent–child functioning. Informed by neuroscience and clinical evidence, sensitive parenting is a vital avenue of intervention that buffers against the toxic effects of COVID-19 on parent–child mental health. In the context of the COVID-19 pandemic, we first discuss the neurobiological, psychological, and behavioral mechanisms behind exacerbated mental health risks in families. We then highlight the role of sensitive parenting as a buffer against stress-related mental health problems, and conclude with recommendations for systemic-, family-, and individual-interventions to most effectively address stress-related mental health problems and their impact on children and families during the COVID-19 pandemic. (PsycInfo Database Record (c) 2021 APA, all rights reserved)