<p>Urbanization represents one of the most significant environmental transformation processes of the 21st century, continuously reshaping the configuration of ecological landscapes on a global scale. This process generates novel ecological conditions that alter the structure and functionality of parasite–host interaction networks, thereby modifying the spatial ecology of zoonotic pathogens such as <i>Trypanosoma cruzi</i>, the etiological agent of Chagas disease. Considering the increase of such transformations, it is critical to integrate a spatial and theoretical framework capable of more accurately modeling the spatial dynamics of this parasite, an endeavor that remains a major challenge in current epidemiological and ecological research. This conceptual review article advocates for the implementation of metapopulation theory as a framework to study and understand the spatial ecology of <i>T. cruzi</i> in human-modified landscapes. It synthesizes current knowledge supporting the potential application of this approach, examining how the parasite’s spatial dynamics in these settings meet core metapopulation principles; outlining future research directions aimed at improving our understanding of the structure, functioning, and persistence of <i>T. cruzi</i> metapopulations. Adopting this conceptual framework not only offers the opportunity for a deeper comprehension of the ecological processes underlying parasite persistence but also provides tools to anticipate risk scenarios and design more effective intervention strategies, tailored to the spatial and temporal dynamics of <i>T. cruzi</i> transmission.</p>