Radiogenic and stable isotopic studies of zircon are a powerful tool to investigate geologic processes because data can be placed in a temporal context using U-Pb ages. However, when zircon data lack information on the spatial distribution of the parent rock(s) (e.g., detrital data sets), interpreting changes in isotopic composition through time is not always straightforward. To evaluate and improve the utility of zircon isotopic data, we present a regional data set consisting of new zircon U-Pb, εHf(t), and δ18Ozrc data in 31 Triassic to early Miocene igneous rocks from a >1300-km-long transect in the southwestern U.S. Cordillera. This data set is combined and compared with a compilation of whole rock isotopic data from the same transect. Orogen-scale spatial and temporal isotopic trends are identified and interpreted, both in terms of the underlying mechanisms that generated the trends and the tectonic processes that have shaped this part of the Cordillera. Most Cordilleran magmatism originates in the upper mantle and zircon εHf(t) primarily reflects the isotopic composition of the mantle source region. East of ∼114°W longitude in the southwestern U.S. Cordillera, the continental mantle lithosphere remained coupled to the crust until the late Miocene and zircon εHf(t) reflects the age of the lithosphere. Because the mantle lithosphere remained intact, zircon εHf(t) and δ18Ozrc of igneous rocks associated with low-angle to flat-slab subduction and crustal thickening during the Laramide orogeny are not significantly different from igneous rocks associated with Farallon slab rollback/foundering. Temporal isotopic trends identified in rocks east of ∼114°W longitude are related to migration of magmatism into lithospheric terranes of a different age. West of ∼114°E longitude, in regions like the Mojave Desert in southern California, USA, the continental mantle lithosphere is interpreted to have been partially removed and replaced by underplated Pelona–Orocopia–Rand schist and isotopically depleted asthenosphere or oceanic lithosphere during the Laramide orogeny. There is a temporal isotopic shift to more juvenile zircon εHf(t) and higher δ18Ozrc in igneous rocks west of ∼114°W, which is used to estimate the position of the western edge of intact North American continental mantle lithosphere before and after the Laramide orogeny. The results suggest that regional (spatial) trends in zircon εHf(t) and δ18Ozrc data can be significantly larger than isotopic shifts at a specific location within a Cordilleran orogenic system. By accounting for regional spatial variations, temporal isotopic trends in zircon data can be more confidently interpreted in terms of tectonic and geodynamics processes.