Basement rocks below the Athabasca Basin, Saskatchewan, have been intensely altered through paleoweathering and multiple hydrothermal events, including the formation of world-class unconformity-type uranium deposits. Here, we demonstrate the utility of Ti-oxide thermochronology for identifying thermotectonic events in these altered rocks leading to uranium mineralization along basement structures. Rutile grains along the P2 fault, a major fault in the eastern Athabasca Basin, exhibit 207Pb/206Pb ages of ca. 1850–1700 Ma, with a weighted mean of 1757 ± 6 Ma (mean square of weighted deviation [MSWD] = 1.4, n = 116). The older ages (>1770 Ma) record regional metamorphism reaching a temperature of 875 °C during the Trans-Hudson orogeny. Pb diffusion modeling indicates that metamorphic rutile should exhibit cooling ages of 1760–1750 Ma. Rutile grains showing young ages, <1750 Ma, reflect isotopic resetting during regional asthenospheric upwelling between 1770 and 1730 Ma related to the emplacement of the Kivalliq igneous suite to the north. This thermotectonic event (temperature > 550 °C) promoted hydrothermal activity to produce silicified rocks, i.e., “quartzite,” along the P2 fault, which later focused mineralizing fluids for unconformity-type uranium deposits. The young rutile ages also indicate that the basement rocks remained hot until 1700 Ma, providing the maximum age for the deposition of the Athabasca sediments. Anatase yields a concordia age of 1569 ± 31 Ma (MSWD = 0.30, n = 5), which is within uncertainty of the oldest ages for uraninite of the McArthur River deposit. This age corresponds to the incursion of basinal fluids in the basement along the P2 fault during uranium mineralization.