Fluvial piracy in the Guadix-Baza basin (southeast Spain) promoted erosion of a high volume of sediments during the late Quaternary, after the former internal drainage of this basin changed to external due to headward erosion by the Guadalquivir River. As a response to load release, this basin underwent uplift, which, in turn, enhanced fluvial incision and erosional processes. Differential erosion within the Guadix-Baza basin resulted in dissimilar isostatic rebound. We numerically model the lithospheric response to sediment unloading and show a total rising of 15 m in the Guadix subbasin compared to 2 m in the Baza subbasin. This differential uplift is likely to have been accommodated along the Baza normal fault, which has been active throughout the Quaternary. Modeling results suggest that ∼13% of the total Quaternary fault throw directly arises from the differential isostatic readjustment between subbasins. This example is one of the first estimates of fault slip partitioning between tectonic and isostatic effects due to unloading driven by river incision.