This article presents the results of archaeological surveys carried out by the Tres Mezquites Project in the Lerma River floodplain at the southwest of the Bajío, Mexico. This research sought to understand settlement dynamics in conjunction with environmental processes in order to recognize the structure of the prehispanic occupation, and to interpret the results within the context of macroregional issues, in particular the social transformations related to the Terminal Preclassic decline of the Chupícuaro culture and the development of Barajas sites during the Epiclassic period. The use of complementary methods combining survey and different types of test pits allowed us to understand and account for biases linked to both sedimentary dynamics and anthropogenic activities. Our results show that the Lerma River was a structuring element for the placement of settlements; the valley foothills were densely occupied, as well as the floodplain, despite the drawbacks of such an environment. The Lerma Valley had a significant occupation from the Terminal Preclassic (A.D. 100–250) to the Epiclassic (A.D. 600–900). The region is located at a strategic point of interface for understanding interactions between the Bajío and the lacustrine regions of Michoacán during the first millennium