The Valle de Santiago (VS) area is located in the NE sector of the Michoacán-Guanajuato Volcanic Field, within the central part of the Trans-Mexican Volcanic Belt (TMVB). Based on geological mapping of a ~2,800 km2 quadrangle, 40Ar/39Ar and radiocarbon dating, morphometry, and whole-rock chemical and petrographic analyses of the volcanic products, we established the stratigraphy and eruptive history of the VS area. A total of 118 volcanic landforms was identified, including 61 scoria cones/ramparts with or without associated lava flows (5.6 vol.%), 21 phreatomagmatic volcanoes (1.8 vol.%), 20 medium-sized shield volcanoes (90.6 vol.%), 8 lava domes (0.7 vol.%), and 8 isolated lava flows (1.3 vol.%). Volcanism in VS began ~8 Ma ago in the NW, with an effusive eruptive style. After a long hiatus (~3 Ma), volcanism resumed in the Pliocene at ~4.9 Ma, culminating in the Late Pleistocene (~11 ka). From the Pliocene to the Middle Pleistocene, volcanism was distributed throughout the VS area, and was predominantly effusive, giving rise to voluminous medium-sized shield volcanoes (e.g., Cerro Grande, Cerro Culiacán, and Picacho-Cerro Prieto). In the Late Pleistocene, volcanism continued in the W of VS, but mainly along an NNW-SSE oriented stripe where phreatomagmatic eruptions dominated. This type of activity was facilitated by fractured aquifers on the slopes of shield volcanoes, and favorable climate conditions during the Late Pleistocene. Erupted products are mainly basaltic andesites/basaltic trachyandesites (52 vol.%), followed by andesites (32.9 vol.%), basalts/trachybasalts (13.8 vol.%), trachyandesites (0.9 vol.%) and rhyolites (0.4 vol.%). Notably, the chemical affinity of the volcanic products shifted over time, transitioning from solely sub-alkaline to both, subalkaline and alkaline by the Late Pleistocene. The VS area holds one of the three largest phreatomagmatic clusters in the entire TMVB, which offers an excellent opportunity to study the conditions favoring phreatomagmatism and provides records of intense volcanic activity during the Plio-Pleistocene.