Abstract Background Podoconiosis, lymphatic filariasis (LF) and leprosy are neglected tropical diseases (NTDs) that cause lymphoedema. When left untreated, they lead to substantial disability. This study determined the quality of life (QOL) and depression associated with lymphoedema in patients with podoconiosis, LF and leprosy. The study was conducted in northwestern Ethiopia. Methods This baseline cross-sectional study, nested within an interventional, non-comparative, longitudinal study, included patients with lymphoedema. Depression and QOL were assessed using versions of the 9-item Patient Health Questionnaire and Dermatologic Life Quality Index (DLQI), respectively, that had been translated into Amharic and validated. Factors associated with depression and QOL were assessed using multivariate linear regression analysis. Results Of the 251 patients with lymphoedema included in the study, 119 (47.4%) had moderate to severe depression and overall QOL was poor (mean±standard deviation [SD] DLQI score: 11.4±4.2). Disability was significantly associated with depression (β=0.26 [95% confidence interval {CI} 0.19 to 0.33]). Currently receiving treatment (β=−3.05 [95% CI −5.25 to −0.85), disability (β=−0.08 [95% CI −0.15 to −0.01]) and social support (moderate support: β=−2.27 [95% CI −3.66 to −0.89] and strong support: β=−2.87 [95% CI −5.35 to −0.38]) were significantly associated with better QOL. Conclusion High levels of depression and low QOL were found among patients with lymphoedema due the three NTDs in Ethiopia.