Devonian strata from the Mackenzie Plain, Northern Canadian Cordillera, have undergone two major burial and unroofing events since deposition, providing an excellent natural laboratory to assess the effects of protracted cooling history on low-temperature thermochronometers in sedimentary basins. Apatite and zircon (U-Th)/He (AHe, ZHe) and apatite fission track (AFT) thermochronology data were collected from seven samples across the Mackenzie Plain. AFT single grain ages from six samples span the Cambrian to Miocene with few Neoproterozoic dates. Although there are no correlations between Dpar and AFT date or track length distribution, a relationship exists between grain chemistry and age. We calculate the parameter rmr0 from apatite chemistry and distinguish up to three discrete kinetic populations per sample, with consistent Cambrian–Carboniferous, Triassic–Jurassic, Cretaceous, and Cenozoic pooled ages. Fifteen ZHe dates range from 415 ± 33 Ma to 40 ± 3 Ma, and AHe dates from 53 analyses vary from 225 ± 14 Ma to 3 ± 0.2 Ma. Whereas several samples exhibit correlations between date and radiation damage (eU), all samples demonstrate varying degrees of intra-sample date dispersion. We use chemistry-dependent fission track annealing kinetics to explain dispersion in both our AFT and AHe data sets and detail the thermal history of strata that have experienced a protracted cooling history through the uppermost crust. Thermal history modeling of AFT and AHe samples reveals that the Devonian strata across the Mackenzie Plain reached maximum burial temperatures (∼90 °C–190 °C) prior to Paleozoic to Mesozoic unroofing. Strata were reheated to lower temperatures in the Cretaceous to Paleogene (∼65 °C–110 °C), and have a protracted Cenozoic cooling history, with Paleogene and Neogene cooling pulses. This thermal information is compared with borehole organic thermal maturity profiles to assess the regional burial history. Ultimately, these data reflect the complications, and possibilities, of low-temperature thermochronology in sedimentary rocks where detrital variance results in a broad range of diffusion and annealing kinetics.