Mesozoic thickening and Cenozoic extension resulted in the juxtaposition of upper and middle crustal rocks in the eastern Mojave Desert, southeastern California and western Arizona. The application of ⁴⁰Ar/³⁹Ar thermochronology to rocks in this region provides information about the timing and nature of thrusting, plutonism, metamorphism, denudation, and detachment faulting. The ⁴⁰Ar/³⁹Ar ages of 175 to 125 Ma from the Clipper, Piute, Turtle, Mohave, Bill Williams, and Hualapai Mountains are interpreted to be the result of a middle Mesozoic thermal event(s) caused by crustal thickening. The ⁴⁰Ar/³⁹Ar data from the Clipper and Piute Mountains suggest that this thermal event was followed by a period of cooling at rates of 1°–5°C/m.y. Orogenesis culminated during the Late Cretaceous when rocks exposed in the Old Woman‐Piute, Chemehuevi, and Sacramento Mountains attained temperatures >500°C which reset the K–Ar systems of minerals from Proterozoic rocks. High‐grade metamorphism in the Old Woman Mountains area was caused by the intrusion of the Old Woman‐Piute batholith at 73±1 Ma. Cooling rates following batholith emplacement in the Old Woman Mountains were ∼100°C/m.y. between 73 and 70 Ma and 5°–10°C/m.y. from 70 to ∼30 Ma. Between 65 and 25 Ma the entire eastern Mojave Desert underwent a period of cooling at a rate of 2°–10°C/m.y. By 30 Ma, rocks exposed in the Old Woman‐Piute, Marble, Ship, Clipper, and Turtle Mountains were below ∼100°C. The ⁴⁰Ar/³⁹Ar ages from the Sacramento Mountains suggest that mylonitization caused by the onset of regional extension occurred at 23±1 Ma. When extension started in the Chemehuevi Mountains, rocks exposed in the southwestern and northeastern portions of footwall to the Chemehuevi detachment fault were at ∼180°C and ∼350°C, respectively. This suggests that the exposed part of the Chemehuevi detachment fault initiated at a dip of 5°–30° or as a series of higher‐angle faults that cut to a depth of 10–12 km and were later rotated to their present dip. Unroofing of the footwalls to detachment faults in the Sacramento and Chemehuevi Mountains resulted in average cooling rates of 10°–50°C/m.y. between 22 and 15 Ma.