Interpretation of the late Cretaceous to Eocene Laramide tectonic evolution of the Colorado Plateau is hampered by the difficulty of placing precise temporal constraints on fault-induced basement uplift, for there is a paucity of exposed basement from which thermochronologic ages might be obtained. The Defiance and Zuni uplifts, located on the southeasternmost Colorado Plateau, offer rare basement exposure that provide additional temporal insights. The Zuni uplift exposes abundant Precambrian basement rock, which has been the subject of previous apatite thermochronologic study to interpret low-temperature tectonic/exhumation history. In the Defiance uplift region, which is the main focus of this study, there are two outcrop areas of Precambrian-basement rock along the trace of the East Defiance monocline. Both sites are quarries. Uplift/erosion consequences of Pennsylvanian-Permian Ancestral Rocky Mountains (ARM) deformation are explicit in the geology of these quarries, for the contact between the Supai Group (Permian) and underlying basement (1,703 ± 1.3 Ma, zircon U-Pb) is a nonconformity. Here, we apply a combination of structural analysis of Laramide fold/fault relations and multi-method thermochronology to the exposed granitic basement of both the Defiance and Zuni uplifts. Zircon U-Pb, zircon (U-Th)/He, apatite fission-track, apatite (U-Th-Sm)/He, and hematite (U-Th)/He reveal a poly-phase thermo-tectonic history. Initially, the Paleo-Proterozoic 1.7 Ga basement cooled to ∼400 °C by at least 1.4 Ga, followed by 1.4–1.0 Ga unroofing to depths of ∼8 km. Following cooling, the Defiance-Zuni granitic basement experienced protracted residence at temperatures ≤200 °C (∼8 km) between <i>ca.</i> 900 and 600 Ma. Sedimentary evidence and hematite (U-Th)/He dates bracket the ARM event (400–200 Ma), which may suggest fluid-rock interaction or near-surface exposure associated with the ARM. Following the ARM, the Defiance uplift experienced heating (>120 °C) associated with burial consistent with the stratigraphic overburden, until approximately 80 Ma. Finally, the Defiance-Zuni region experienced initial cooling at <70 Ma, with the main phase of exhumation to the upper crust (<2 km) at <i>ca.</i> 60–40 Ma. Detailed structural modeling along 15 normal-profile cross-sections across the east margin of the Defiance uplift reveals that Laramide trishear monoclinal folding was generated by an oblique-slip master fault that partitioned ∼8 km of strike-slip and ∼1.5 km of reverse-slip displacement. Inferred strike-slip compartmental faulting in the Zuni uplift appears to fit coherently within this overall kinematic model in relation to Laramide loading direction. In the context of geodynamic models for flat-slab subduction during the Laramide tectonic event, consideration of new data from the Defiance uplift (along with other recently reported thermochronology data) provides support for models that bring the flat slab beneath North America along an east-northeastward trajectory, rather than along a more northward trajectory.