BackgroundThe COVID-19 pandemic has profoundly impacted the economic, psychological, and social well-being of people in Ethiopia. Pandemic-related fears can exacerbate anxiety and depression symptoms among those with pre-existing physical and mental health conditions as well as those with prior exposure to traumatic events. MethodsWe used data from the Ethiopia NeuroGAP-Psychosis study (898 cases and 941 controls with and without a diagnosis of psychosis respectively, 66% male, mean age = 37 years). Data was collected between November 2021 and June 2022 during the COVID-19 pandemic from four hospitals in Ethiopia (three in Addis Ababa and one in Jimma city). Structural equation modeling analysis was conducted to examine the associations between trauma exposure, physical health conditions (like arthristis, neurological disorders, diabetes), COVID-19 stress, and psychological distress (depression and anxiety symptoms). We assessed direct and indirect effects for mediation, and conducted multigroup analysis to examine moderation by case control status. ResultsWe found evidence that the impact of greater trauma exposure and physical health conditions on higher psychological distress was mediated through higher COVID-19 stress. Sociodemographic characteristics (older age and being maried) were associated with higher psychological distress, with these associations mediated through greater trauma, physical health conditions, and COVID-19 stress. Case-control status also moderated the associations between these variables, with the mediation effects being stronger in cases and weaker in controls. Further, cases reported greater trauma and psychological distress, while controls reported more physical health conditions and COVID-19 stress. ImplicationsOur findings uniquely assess the interaction of health and emergency related factors in understudied settings like Ethiopia. They underscore the importance of including daily hardships and environmental stressors, along with prior trauma exposure, as risk factors for the assessment of mental health symptoms. This study has key implications for mental health screening and intervention research in response to complex emergency contexts like Ethiopia with a history of armed conflict in addition to the COVID-19 pandemic. Our findings can aid the development of targeted services that address the mental health of at-risk groups with pre-existing mental and physical health conditions.