The pattern and timing of deformation in southeast Tibet resulting from the early stages of the India-Asia collision are crucial factors to understand the growth of the Tibetan Plateau, but they remain poorly constrained. Detailed field mapping, structural analysis, and geochronological and thermochronological data along a 120 km section of the Ludian-Zhonghejiang fold-and-thrust belt bounding the Jianchuan basin in western Yunnan, China, document the early Cenozoic tectonic evolution of the conjunction between the Lanping-Simao and South China blocks. The study area is cut by two major southwest-dipping brittle faults, named the Ludian-Zhonghejiang fault and the Tongdian fault from east to west. Numerous kinematic indicators and the juxtaposition of Triassic metasedimentary rocks on top of Paleocene strata indicate thrusting along the Ludian-Zhonghejiang fault. Similarly, structural analysis shows that the Tongdian fault is a reverse fault. Between these structures, fault-bounded Permian–Triassic and Paleocene rocks are strongly deformed by nearly vertical and upright southwest-vergent folds with axes that trend nearly parallel to the traces of the main faults. Zircon and apatite (U-Th)/He and apatite fission-track data from a Triassic pluton with zircon U-Pb ages of 237–225 Ma in the hanging wall of the Ludian-Zhonghejiang fault, assisted by inverse modeling, reveal two episodes of accelerated cooling during 125–110 Ma and 50–39 Ma. The Cretaceous cooling event was probably related to crustal thickening during the collision between the Lhasa and Qiangtang terranes. The accelerated exhumation during 50–39 Ma is interpreted to record the life span of the fold-and-thrust belt. This timing is corroborated by the intrusive relationship of Eocene magmas of ca. 36–35 Ma zircon U-Pb age into the fold-and-thrust belt. Early Cenozoic activity of the deformation system controlled deposition of alluvial-fan and braided-river sediments in the Jianchuan basin, as evidenced by eastward and northeastward paleoflows and terrestrial clasts derived from the hanging wall of the Ludian-Zhonghejiang thrust. Since 39 Ma, decreasing cooling rates likely reflect cessation of activity on the fold-and-thrust belt. Early Cenozoic compressive deformation on the western margin of the South China block together with geological records of contraction in central, northern, and eastern Tibet document Eocene upper-crustal shortening located in the Himalaya, Qiangtang terrane, and northern plateau margins together with contractional basin development in the intervening Lhasa, Songpan-Garze, and Kunlun terranes, coeval with or shortly after the onset of the India-Asia collision. This suggests that moderate crustal shortening affected a large part of Tibet in a spaced way, contrary to models of homogeneous crustal thickening soon after the collision, and prior to the main crustal thickening, propagating progressively from south to north. This complex deformation pattern illustrates the complexity of Asian crustal rheology, which contrasts with assumptions in existing geodynamic models.