Background Human transmission of Chagas disease (CD) most commonly occurs in domiciliary spaces where triatomines remain hidden to feed on blood sources during inhabitants’ sleep. Similar to other neglected tropical diseases (NTDs), sustainable control of CD requires attention to the structural conditions of life of populations at risk, in this case, the conditions of their living environments. Considering socio-cultural and political dynamics involved in dwellings’ construction, this study aimed to explore social factors that contribute or limit sustainability of CD’s prevention models focused on home improvement. Methods and main findings Using Healthy Homes for Healthy Living (HHHL)—a health promotion strategy focused on improvement of living environments and system-based health promotion—as a reference, a qualitative study was conducted. Research participants were selected from three rural communities of a CD endemic region in southern Ecuador involved in HHHL’s refurbishment and reconstruction interventions between.