The relationship between Andean uplift and extreme desiccation of the west coast of South America is important for understanding the interplay between climate and tectonics in the Central Andes, yet it is poorly understood. Here we use soil morphological characteristics, salt chemistry, and mass independent fractionation anomalies (Δ17O values) in dated paleosols to reconstruct a middle Miocene climatic transition from semiaridity to extreme hyperaridity in the Atacama Desert. Paleosols along the southeastern margin of the Calama Basin change from calcic Vertisols with root traces, slickensides, and gleyed horizons to an extremely mature salic Gypsisol with pedogenic nitrate. We interpret this transition, which occurred between 19 and 13 Ma, to represent a change in precipitation from >200 mm/yr to <20 mm/yr. This drastic reduction in precipitation likely resulted from uplift of the Central Andes to elevations >2 km; the uplift blocked moisture from the South American summer monsoon from entering the Atacama. The mid-Miocene Gypsisol with pedogenic nitrate is located at elevations between 2900 and 3400 m in the Calama Basin, significantly higher than modern nitrate soils, which occur below ∼2500 m. Modern and Quaternary soils in this elevation zone contain soil carbonate and lack pedogenic gypsum and nitrate. We infer that >900 m of local surface uplift over the past 10 m.y. displaced these nitrate paleosols relative to modern nitrate soils and caused a return to wetter conditions in the Calama Basin by decreasing local air temperatures and creating an orographic barrier to Pacific air masses.