Responding to families at heightened risk for mental health burdens during the COVID-19 pandemic is critical-evidence suggests parents face elevated burdens compared to their nonparent counterparts. Building on studies that demonstrate a spillover of stress across domains and individuals within families, this study examines longitudinal predictors of elevated risks for clinical depression among parents based on relational family indicators, COVID-specific stressors, and stress and emotion regulation indicators. Baseline data were collected from parents (n = 176; average age 37.04, 50% female) on April 27-28, 2020, 5 weeks after the first U.S. quarantines began. Follow-up data were collected 30 days later. Results indicated concerning levels of parents' mental health symptoms over this short time span, including elevated stressors and exacerbated mental health symptoms for approximately one-quarter of parents. Given the need for agile service responses for those at the greatest risk, this article examines predictions of clinically significant depression through binary logistic regression. These individuals were more likely to report greater anxiety and stress symptoms, as well as report less closeness in their parent-child relationships; couple satisfaction was not a significant predictor of depression. Implications include recommended agile responses to alleviate distress and expand access to mental health supports, particularly in light of pervasive shelter-in place orders that limit access to previously established coping supports and sources of social connection (e.g., schools or community centers), that are anticipated to recur in the months ahead.