The spatial and temporal distribution of Pliocene to Holocene Colorado River deposits (southwestern USA and northwestern Mexico) form a primary data set that records the evolution of a continental-scale river system and helps to delineate and quantify the magnitude of regional deformation. We focus in particular on the age and distribution of ancestral Colorado River deposits from field observations, geologic mapping, and subsurface studies in the area downstream from Grand Canyon (Arizona, USA). A new 4.73 ± 0.17 Ma age is reported for a basalt that flowed down Grand Wash to near its confluence with the Colorado River at the eastern end of what is now Lake Mead (Arizona and Nevada). That basalt flow, which caps tributary gravels, another previously dated 4.49 ± 0.46 Ma basalt flow that caps Colorado River gravel nearby, and previously dated speleothems (2.17 ± 0.34 and 3.87 ± 0.1 Ma) in western Grand Canyon allow for the calculation of long-term incision rates. Those rates are ~90 m/Ma in western Grand Canyon and ~18–64 m/Ma in the eastern Lake Mead area. In western Lake Mead and downstream, the base of 4.5–3.5 Ma ancestral Colorado River deposits, called the Bullhead Alluvium, is generally preserved below river level, suggesting little if any bedrock incision since deposition. Paleoprofiles reconstructed using ancestral river deposits indicate that the lower Colorado River established a smooth profile that has been graded to near sea level since ca. 4.5 Ma. Steady incision rates in western Grand Canyon over the past 0.6–4 Ma also suggest that the lower Colorado River has remained in a quasi–steady state for millions of years with respect to bedrock incision. Differential incision between the lower Colorado River corridor and western Grand Canyon is best explained by differential uplift across the Lake Mead region, as the overall 4.5 Ma profile of the Colorado River remains graded to Pliocene sea level, suggesting little regional subsidence or uplift. Cumulative estimates of ca. 4 Ma offsets across faults in the Lake Mead region are similar in magnitude to the differential incision across the area during the same approximate time frame. This suggests that in the past ~4 Ma, vertical deformation in the Lake Mead area has been localized along faults, which may be a surficial response to more deep-seated processes. Together these data sets suggest ~140–370m of uplift in the past 2–4 Ma across the Lake Mead region.