The COVID-19 pandemic puts health workers at increased risk of adverse mental health outcomes. However, no studies have assessed health workers’ experiences using qualitative methods during the COVID-19 outbreak in the United States to identify novel factors that could relate to their mental health. In May 2020, we distributed an online survey to health workers across 25 medical centers throughout the United States. The Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Primary Care-Post-Traumatic Stress Disorder, and Alcohol Use Disorders Identification Test-Concise and associated cutoff values were used to assess rates of probable major depression, generalized anxiety disorder, post-traumatic stress disorder, and alcohol use disorder, respectively. To provide insight into the factors shaping these and other mental health conditions, we included two open-ended questions asking respondents to recount their most upsetting and hopeful experiences during the COVID-19 pandemic and how it made them feel. Using a hybrid inductive-abductive approach and thematic content analysis, we created a Social Ecological Model to represent themes among health workers’ experiences within five ecological levels: individual, interpersonal, organization, community, and public policy. Of the 1,132 participants who completed the survey, 14.0% had probable major depression, 15.8% probable generalized anxiety disorder, 23.1% probable post-traumatic stress disorder, and 42.6% probable alcohol use disorder. Individual level themes included participants’ personal health and self-care behaviors. Interpersonal level themes included the health of their social circle, family functioning, and social support. Organization level themes included their hospital’s management, resources, patient care, routine, and teams. Themes in the community level included the media, scientific knowledge about COVID-19, morale, behavior, and support of health workers. Lastly, government and health system leadership and shelter-in-place policy were themes within the public policy level. Our findings provide insights into novel factors that have impacted health workers’ wellbeing during the COVID-19 pandemic. These factors should be further explored to inform interventions and public policy that mitigate mental health morbidities among health workers during this and future outbreaks.