Constraining the uplift and exhumation history of the Venezuelan Andes is critical for understanding the complex geodynamic evolution of northern South America. We present new apatite fission-track (AFT) data from the Sierra Nevada de Mérida in the central Venezuelan Andes and compare the results with previously published AFT data for the Sierra La Culata (El Carmen block) to the north. The AFT data are combined with three-dimensional thermal modeling to constrain the exhumation and relief history of both blocks, which show significant differences. The Sierra Nevada indicates exhumation rates of ∼1.7 km/m.y. from ca. 10 Ma until 4 Ma, decreasing to ∼0.4 km/m.y. from 4 Ma to present; the El Carmen block, in contrast, underwent much more rapid recent exhumation, with rates of ∼1.4 km/m.y. since 4 Ma. The data suggest ∼4 km of relative rock uplift of the Sierra La Culata with respect to the Sierra Nevada since 4 Ma and support significant uplift of basement blocks along major preexisting discontinuities during transpression in the Northern Andes, linked to accretion of the Panama arc and indentation of the Maracaibo block. Rapid Middle–Late Miocene exhumation in the Sierra Nevada resulted from surface uplift that caused the Late Miocene deflection of the Orinoco River inferred from the Neogene sedimentary record.