Abstract Background Leprosy, cutaneous leishmaniasis (CL) and Chagas disease (CD) are neglected tropical diseases (NTDs) with a high psychosocial burden in Norte de Santander and Arauca in Colombia. This study provides insights into affected persons' feelings, perceptions and experiences to better understand the nature of this burden. Methods In 2018, 34 leprosy, CD and CL patients participated in four focus groups discussing the influence of the disease on mental well-being, social participation and stigma. Additionally, 13 leprosy patients participated in semi-structured interviews to further explore the health-related stigma related to this disease. Audio recordings were transcribed verbatim, and open coding was used to identify the most relevant categories and themes. Results Persons suffering from CD reported that their mental distress was mainly caused by impairments and stress related to the progressive and incurable nature of the disease. Persons affected by CL perceived the treatment for the disease as having the most impact on their psychosocial well-being. Persons affected by leprosy reported suffering most from anticipated and experienced stigma. Conclusions The findings indicate that these diseases are likely to impose a significant psychosocial burden on patients in the studied regions, even though these vary per condition. Consistent data collection on the psychosocial burden and the sharing of knowledge of effective interventions can contribute to the holistic approach needed to win the fight against NTDs.