Although the Ethiopian Plateau is a prominent feature in East Africa, its exhumation history is not well constrained. For the last few decades, this history has been a topic of scientific interest due to the plateau's complicated geologic setting and thermal response to surface topographic changes. Studies of the plateau's thermal history have the potential to cast light on the numerous tectonic and geodynamic events that have affected the region since the beginning of the Mesozoic, such as Gondwana rifting, Afar mantle plume upwelling, continental flood basalt emplacement, Cenozoic continental rifting, and shield and cinder cone volcanism that has continued until the present day. We present new single-grain apatite (U-Th)/He (AHe) thermochronologic cooling ages from the Blue Nile Canyon to address the Ethiopian Plateau's exhumation history. AHe dates of 55 grains from nine Neoproterozoic basement and Mesozoic sedimentary rock samples, collected from a vertical transect of the Blue Nile Canyon, range from 58.9 ± 2.7 to 460.2 ± 34.7 Ma. Interpretation of these cooling ages is complex due to intra-sample age dispersion. We address this dispersion by systematically evaluating the ages based on standard deviation percentage, effective Uranium concentration [eU], and equivalent spherical grain radius r, which also helps select samples to generate a geologically meaningful thermal history model. Our inverse thermal history model using the Radiation Damage Accumulation and Annealing Model (RDAAM) reveals a protracted Paleozoic cooling, a gradual reheating during Permo-Mesozoic time (between ∼300 and ∼100 Ma), and a rapid cooling in the Cretaceous (∼100 Ma). This Paleozoic and Mesozoic thermal history reflects post-Pan-African orogenic denudation followed by Gondwana rift-related burial and then exhumation. A period of tectonic quiescence is reflected between ∼100 and ∼30 Ma, during which there was little to no cooling. Although our thermal model shows burial-related reheating after the flood basalt emplacement around 30 Ma and eventual cooling to present-day surface temperature, our thermochronologic data likely lack sufficient resolution to determine the details of the Neogene cooling related to incision of the Blue Nile Canyon. Our study suggests that the thermal history of the Ethiopian Plateau is dynamic and warrants further high-resolution, low-temperature thermochronologic investigation to constrain post-30 Ma river incision of the plateau.