The Great Unconformity (GU), a global erosion surface separating Precambrian and Paleozoic rocks, represents ∼100–1000 m.y. of missing geologic time. The timing of erosion and amount of denudation leading to the formation of the GU remains largely unknown, but could provide important constraints to models of cratonic vertical movements during the supercontinent cycle, and estimates of sediment production that influenced Neoproterozoic ocean-atmosphere chemistry. The Ozark Plateau in the North America craton exposes ca. 1400 Ma granite below ca. 500 Ma sandstone. We quantify the timing and rates of basement cooling (as an exhumation proxy) at this location by using zircon (U-Th)/He thermochronology and a model describing coevolution of radiation damage and helium diffusion in zircon. This approach reveals Precambrian exhumation phases from a minimum depth of ∼6 km ca. 850–680 Ma. Complementary apatite (U-Th)/He and fission track data record younger exhumation at ca. 225–150 Ma, as detected by previous studies. These denudation phases coincide with Rodinia and Pangea supercontinent break up, a result that implies a genetic relation between continental uplift and phases in the supercontinent cycle, and supports correlations relating snowball Earth cooling to increased weathering and CO2 drawdown.