Background: On March 5th, Guatemala declared a 'State of Calamity' in response to the COVID-19 pandemic and strict lockdown measures were initiated. The psychological consequences of these measures are yet to be fully understood. There is limited research on the psychological impact of the virus in the general population, and even less focused on Latin America and high-risk communities characterized by poverty, limited mental health resources, and high rates of stigma around mental illness. The goal of this study is to examine the psychological impact of COVID-19 across several highly vulnerable districts in Guatemala. Methods: A semi-structured phone interview was conducted of 295 individuals in multiple districts in Guatemala City to assess self-perceived mental health consequences related to the pandemic. Sociodemographic, medical, and mental health data were collected. Chisquares and t-tests used for categorical and continuous variables, as appropriate, to describe the sample. Binary logistic regressions were estimated to examine associations between sociodemographic characteristics and mental health symptoms (anxiety, stress, depression, burnout, escalation of pre-existing mental health symptoms, and a sense of safety). Results: The results indicate high levels of anxiety and stress in all target communities. Significant differences based on gender, age, and the number of children in the household were identified: women and older adults experience higher rates of stress and anxiety associated with the pandemic; while families with greater number of children experience higher levels of burnout. Conclusion: Contextualizing the current pandemic as a complex emergency can help inform further studies focusing on socioeconomic challenges and higher vulnerabilities as preconditions affecting the impact of the pandemic on mental health. Given the limited available resources for mental health care in Guatemala, informal networks of care may play an important role in meeting the needs of those individuals experiencing increased psychological distress resulting from the pandemic.