Uplift and amalgamation of the high-elevation (>3000 m) Tian Shan and Pamir ranges in Central Asia restricts westerly atmospheric flow and thereby limits moisture delivery to the leeward Taklimakan Desert in the Tarim Basin (<1500 m), the second largest modern sand dune desert on Earth. Although some research suggests that the hyper-arid conditions observed today in the Tarim Basin developed by ca. 25 Ma, stratigraphic evidence suggests the first erg system did not appear until 12.2 Ma. To address this controversy and to understand the tectonic influences on climate in Central Asia, we studied a continuous, 3800-m-thick stratigraphic section deposited from 15.1 to 0.9 Ma now exposed within the western Kepintagh fold-and-thrust belt in the southern Tian Shan foreland. We present new detrital zircon data (n = 839), new carbonate oxygen (δ18Oc) and carbon (δ13Cc) stable isotope compositions (n = 368), structural modeling, and stratigraphic observations, and combine these data with recently published magnetostratigraphy and regional studies to reconstruct the history of deposition, deformation, and climate change in the northwestern Tarim Basin. We find that basins along the southern (this study) and northern (i.e., Ili Basin) margins of the Tian Shan were likely receiving similar westerly precipitation by 15 Ma (δ18Oc = ~–8‰) and had similar lacustrine-playa environments at ca. 13.5 Ma, despite differences in sedimentary provenance. At ca. 12 Ma, an erg desert formed adjacent to the southern Tian Shan in the northwestern Tarim Basin, coincident with a mid-to late Miocene phase of deformation and exhumation within both the Pamir and southern Tian Shan. Desertification at ca. 12 Ma was marked by a negative δ18Oc excursion from −7.8 ± 0.4‰ to −8.7 ± 0.7‰ in the southern Tian Shan foreland (this study), coeval with a negative δ18Oc excursion (~–11 to −13‰) in the Tajik Basin, west of the Pamir. These data suggest that only after ca. 12 Ma did the Pamir-Tian Shan create a high-elevation barrier that effectively blocked westerly moisture, forming a rain shadow in the northwestern Tarim Basin. After 7 Ma, the southern Tian Shan foreland migrated southward as this region experienced widespread deformation. In our study area, rapid shortening and deformation above two frontal foreland faults initiated between 6.0 and 3.5 Ma resulted in positive δ13Cc excursions to values close to 0‰, which is interpreted to reflect exhumation in the Tian Shan and recycling of Paleozoic carbonates. Shortening led to isolation of the study site as a piggy-back basin by 3.5 Ma, when the sediment provenance was limited to the exhumed Paleozoic basement rocks of the Kepintagh fold belt. The abrupt sedimentologic and isotopic changes observed in the southern Tian Shan foreland appear to be decoupled from late Cenozoic global climate change and can be explained entirely by local tectonics. This study highlights how tectonics may overprint the more regional and global climate signals in active tectonic settings.