Several types of critical mineral-bearing ore deposits in the southern Midcontinent region of the U.S. are hosted in Mesoproterozoic igneous rocks largely concealed beneath Paleozoic cover. Discerning the architecture of igneous intrusions and volcanic centers in the crust is fundamental to understanding the geologic evolution of this vast region and its mineral resources. To advance the understanding of the geologic framework beneath the Southeast Missouri Iron Metallogenic Province, we invert continental-scale magnetic and gravity anomaly data to three-dimensional (3D) physical property models. The regional models image altered and mineralized igneous rocks near the Precambrian basement surface and underlying intrusive complexes that extend down to the Moho. At shallow crustal levels, our models confirm that iron oxide-apatite ± rare earth element (IOA±REE) deposits and iron oxide-copper-gold ± cobalt (IOCG) deposits occur within or near the edges of large low density/low susceptibility early Mesoproterozoic (ca 1.4 Ga) silicic calderas and (ca 1.3 Ga) granitic plutons. Previous isotopic and geochemical studies conclude that the iron deposits and their volcanic host rocks originated from mantle-derived and crustal melts that erupted during regional extension. Extension was associated with thermal event(s) that produced the large-scale silicic magmatism related to the ca 1.45 Ga Eastern Granite Rhyolite Province (EGRP) and the 1.35 Ga Southern Granite Rhyolite Province (SGRP). We postulate that early in the evolution of the EGRP, several trans-crustal magmatic plumbing systems developed that are evident in the 3D models. The Southeast Missouri Metallogenic Province is underlain by one such magmatic system that is expressed as a northwest-trending ~ 50 km-wide by 200 km-long elongate track of high susceptibility at deep crustal levels. The high susceptibility corridor splays upward through the crust to the Precambrian surface where the iron deposits are the epigenetic manifestation of this magmatic event. Our findings confirm that the iron deposits, with no distinct connection at the surface, are connected to one large magmatic system at depth. We propose that other similar susceptibility tracks, which are present along the top of the mantle, mark additional feeder zones that allowed magma to ascend to the main eruptive centers that produced the Granite Rhyolite Provinces. The early Mesoproterozoic extensional tectonic framework established crustal-scale pathways that controlled the distribution of subsequent magmatic activity, including the ca 1.4 Ga calderas and underlying intrusions, ca 1.3 Ga silicic plutons and Phanerozoic alkaline intrusions. If these interpretations are correct, our study has identified large areas that are prospective for critical mineral-bearing ore deposits and, importantly, suggests that the Mesoproterozoic architecture may have influenced subsequent magmatism and hydrothermal activity in the southern Midcontinent of the U.S.