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BACKGROUND: Depression and burnout are common among healthcare workers (HCWs) and negatively affect their wellbeing and the quality of the service they provide. However, the burden of depression and burnout among health extension workers (HEWs) in Ethiopia and their relationship has not been documented well. The objective of this study was to estimate the prevalence of depression and burnout among HEWs in Ethiopia and to investigate the relationship between these conditions. MATERIALS AND METHODS: We used a cross-sectional study design and collected data from 584 rural and 581 urban HEWs in Ethiopia, as part of the 2019 national health extension program assessment. The Patient Health Questionnaire (PHQ-9) and Burnout Self-Test were used to screen HEWs for depression and burnout, respectively. We used descriptive statistics to estimate the magnitude of depression and burnout, and logistic regression to examine their relationship. RESULT: Based on PHQ-9 cutoff scores of 10, the prevalence of major depression was 16.5% among rural and 8.9% among urban HEWs, whereas burnout risk was 39.8% among rural and 12.6% among urban HEWs. The odds of having depression among HEWs with burnout risk was relatively higher compared to those without burnout risk [For rural HEWs, the adjusted odds ratio (AOR) is 11.88 at a 95% confidence interval (CI; 5.27, 26.80), and for urban HEWs, the AOR is 11.49 at a 95% CI (5.35, 24.63)]. CONCLUSION: The prevalence of depression and burnout is high among HEWs in Ethiopia, with a significant rural–urban difference, and burnout is a significant predictor of depression. Mental health interventions that enable prevention, early detection, and management are needed especially for rural HEWs who are in charge of preventive health service delivery for the disadvantaged rural communities. [ABSTRACT FROM AUTHOR]