Buruli ulcer, caused by Mycobacterium ulcerans, is a neglected tropical skin disease that is primarily endemic in West and Central Africa, including Côte d'Ivoire. Studies indicate that M. ulcerans infections are caused by contact with an environmental reservoir of the bacteria, governed by specific human biological conditions. Yet, the nature of this reservoir and the exact mode of transmission remain unknown. To identify ecologic risk factors of Buruli ulcer in south-central Côte d'Ivoire, we pursued a qualitative study matched with geo-referencing inquiry. Embedded in a broader integrated wound management research project, we (i) mapped households and water sources of laboratory confirmed Buruli ulcer cases and (ii) interviewed 12 patients and four health care workers to assess exposure to surface water and to deepen the understanding of perceived transmission pathways. Water availability, accessibility, and affordability were reported as key determinants for choosing water resources. Furthermore, perceived risks were related to environmental, structural, and individual factors. Despite the presence of improved water sources (e.g., drilled wells), communities heavily relied on unprotected surface water for a multitude of activities. The nearby Bandama River and seasonal waterbodies were frequently used for washing, bathing, and collection of water for drinking and cooking. Many residents also reported to cross the river on a daily basis for agricultural chores, and hence, are exposed to stagnant water during farming activities. Our study in two Buruli ulcer endemic villages in south-central Côte d'Ivoire revealed a wide range of water-related domestic activities that might expose people to an increased risk of contracting the disease. Environmental, biological, social, and cultural risk factors are closely interlinked and should be considered in future investigations of Buruli ulcer transmission. Active participation of the communities is key to better understand their circumstances to advance research and fight against Buruli ulcer and other neglected tropical diseases.