Evidence suggests parents experience unique pandemic-related stressors related to isolation, food insecurity, school closures, and unemployment. This study examined 1,048 U.S. parents’ depression, anxiety, stress, and alcohol and substance use behaviors during March and April 2020 to better understand the impact of pandemic-related conditions on parents’ mental health. Mean scores indicated severe levels of depression and stress and extremely severe anxiety. Nearly two thirds (74.7%) indicated alcohol use in the past month, with 26.5% scoring in the range for problem alcohol use. Almost half of the sample reported using at least one substance in the previous 2 weeks. Men had significantly higher alcohol consumption and substance use than women. Depression, anxiety, and stress were higher for parents who consumed alcohol or substances and had a history of depression or anxiety. The long-term impact of COVID-19 is unknown, and mental health care is likely to be in high demand moving forward.