Magmatism in northern Colorado beginning in the late Eocene is associated with the formation of Pb-Zn-Ag carbonate-replacement and polymetallic vein deposits, the onset of caldera-forming magmatism, and eventually, the formation of rift-related, F-rich Mo porphyries (“Climax-type” intrusions). We use high-precision U/Pb zircon geochronology to better evaluate the temporal framework of magmatism and mineralization in the region. Our results demonstrate that mineralization in the Leadville area occurred between 43.5 and 39.7 Ma and was followed by mesothermal mineralization in the Montezuma area at approximately 38.7 Ma. Mineralization is associated with a suite of approximately 43 to 39 Ma intermediate magmatic centers that extended from Twin Lakes through Montezuma. The oldest porphyries associated with F-rich Mo prospects and deposits (Middle Mountain; 36.45 Ma) intruded 900 kyr after the start of the ignimbrite flare-up in the region. Spatiotemporal analyses reveal that the pattern of magmatism shifted in orientation between 40 and 35 Ma. We propose a model wherein magmatism before 39 Ma was the result of fluids evolved from the subducted Farallon slab being focused through weak zones in the lithospheric mantle and into the lower crust. This was followed by a more diffuse and higher power melting event that corresponds to a distinct change in the spatial patterns of magmatism. Our data suggest that low-grade Mo porphyry deposits can form close in time to calderas. We hypothesize that the transition from subduction to extensional tectonics in the region was responsible for this more widespread melting and a distinct shift in the style of magmatic-hydrothermal mineralization.