Structural, stratigraphic, and thermochronologic studies provide insight into the formation of basement-cored uplifts within the Colorado Plateau–Basin and Range transition zone in the Lake Mead region. Basement lithologic contacts, foliations, and ductile shear zones preserved in the core of the Virgin Mountain anticline parallel the trend of the anticline and are commonly reactivated by brittle fault zones, implying that basement anisotropy exerted a strong influence on the uplift geometry of the anticline. Potassium feldspar ⁴⁰Ar/³⁹Ar thermochronology indicates that basement rocks cooled from ≥250–325 °C to ≤150 °C in the Mesoproterozoic and remained at shallow crustal levels (<5–7 km) until they were exhumed to the surface. Apatite fission-track ages and track length measurements reveal a transition from slow cooling beginning at 30–26 Ma to rapid cooling at ca. 17 Ma, which we interpret to mark the change from regional post-Laramide denudational cooling to rapid extension-driven exhumational cooling by ca. 17 Ma. Middle Miocene conglomerates (ca. 16–11 Ma) flanking the anticline contain locally derived basement clasts with ca. 20 Ma apatite fission-track ages, implying rapid exhumation rates of ≥500 m m.y.⁻¹. The apparently complex geometry of the anticline resulted from the superposition of first-order processes, including isostatic footwall uplift and extension-perpendicular shortening, on a previously tectonized and strongly anisotropic crust. A low-relief basement-cored uplift may have formed during the Late Cretaceous–early Tertiary Laramide orogeny; however, the bulk of uplift, exhumation, and deformation of the Virgin Mountain anticline occurred during middle Miocene crustal extension.