Chagas disease, caused by the protozoa Trypanosoma cruzi, is an important yet neglected disease that represents a severe public health problem in the Americas. Although the alteration of natural habitats and climate change can favor the establishment of new transmission cycles for T. cruzi, the compound effect of human-modified landscapes and current climate change on the transmission dynamics of T. cruzi has until now received little attention. A better understanding of the relationship between these factors and T. cruzi presence is an important step towards finding ways to mitigate the future impact of this disease on human communities. Here, we assess how wild and domestic cycles of T. cruzi transmission are related to human-modified landscapes and climate conditions (LUCC-CC). Using a Bayesian datamining framework, we measured the correlations among the presence of T. cruzi transmission cycles (sylvatic, rural, and urban) and historical land use, land cover, and climate for the period 1985 to 2012. We then estimated the potential range changes of T. cruzi transmission cycles under future land-use and -cover change and climate change scenarios for 2050 and 2070 time-horizons, with respect to “green” (RCP 2.6), “business-as-usual” (RCP 4.5), and “worst-case” (RCP 8.5) scenarios, and four general circulation models. Our results show how sylvatic and domestic transmission cycles could have historically interacted through the potential exchange of wild triatomines (insect vectors of T. cruzi) and mammals carrying T. cruzi, due to the proximity of human settlements (urban and rural) to natural habitats. However, T. cruzi transmission cycles in recent times (i.e., 2011) have undergone a domiciliation process where several triatomines have colonized and adapted to human dwellings and domestic species (e.g., dogs and cats) that can be the main blood sources for these triatomines. Accordingly, Chagas disease could become an emerging health problem in urban areas. Projecting potential future range shifts of T. cruzi transmission cycles under LUCC-CC scenarios we found for RCP 2.6 no expansion of favourable conditions for the presence of T. cruzi transmission cycles. However, for RCP 4.5 and 8.5, a significant range expansion of T. cruzi could be expected. We conclude that if sustainable goals are reached by appropriate changes in socio-economic and development policies we can expect no increase in suitable habitats for T. cruzi transmission cycles.