El Astillero and El Pedregal monogenetic volcanoes formed ∼500–700 CE in the Tancítaro region in the southern part of the Michoacán-Guanajuato volcanic field, only 25 km to the SW of the historic Paricutin volcano. The ∼6-year-long eruption was characterized by a change from explosive to effusive activity, accompanied by a shift in the location of the active vents. Initial activity was Strombolian-explosive and first formed the El Astillero cone before turning effusive with the emission of several lava flows. Then, a new vent located 2 km to the ENE opened and produced the purely effusive (non-explosive) El Pedregal lava flow field. As the eruption progressed, the bulk magma composition (major and trace elements) changed from basaltic andesite to andesite (SiO2 = 52–59 wt%), which is also reflected in a successive change in the petrography of the erupted tephras and lavas. However, the El Pedregal lava sequence shows small Mg# reversals followed by a marked final reversal to more mafic compositions. Likewise, 87Sr/86Sr (0.70388–0.70403), 143Nd/144Nd (0.512836–0.512742), 206Pb/204Pb (18.632–18.671), 207Pb/204Pb (15.583–15.598), 208Pb/204Pb (38.376–38.450), 176Hf/177Hf (0.28301–0.28290), and 187Os/188Os (0.1258–0.1865) isotope ratios changed systematically as the eruption progressed, and record a final shift to a distinct isotopic signature. The spatio-temporal proximity of both vents and the petrographic and geochemical characteristics of their magmas suggest a comagmatic evolution that can be explained by a combination of variable degrees of magma recharge, magma mixing, and fractional crystallization of subduction-modified mantle melts. A similar combination of magmatic processes for the genesis and evolution of these magmas has also been proposed for other young monogenetic volcanoes in the Michoacán-Guanajuato volcanic field (e.g., Paricutin, Jorullo, and the Tacámbaro cluster). Accordingly, primitive magmas in the Trans-Mexican Volcanic Belt are subduction-modified mantle melts that evolve largely by crystal fractionation and pass through the crust without significant assimilation.