The Qaidam basin is the largest topographic depression inside the Tibetan plateau. Because of its central position, understanding the tectonic origin of the Qaidam basin has important implications for unraveling the formation mechanism and growth history of the Tibetan plateau. In order to achieve this goal, we analyzed regional seismic-reflection profiles across the basin and a series of thickness-distribution patterns of Cenozoic strata at different time slices. The first-order structure of the basin is a broad Cenozoic synclinorium, which has an amplitude ranging from >16 km in the west to <4 km in the east. The synclinorium has expanded progressively eastward across the Qaidam region: from the western basin against the Altyn Tagh fault at 65–50 Ma to the eastern basin at 24 Ma. The half-wavelength of the regional fold complex changes from ~170 km in the west to ~50 km in the east. The formation of the synclinorium was induced by an older thrust system initiated ca. 65–50 Ma in the northern margin and a younger thrust system initiated ca. 29–24 Ma in the southern basin margin. Cenozoic upper-crustal shortening decreases eastward across basin from >48% in the west to <1% in the east; the associated strain rates vary from 3.2 × 10−15 s−1 to 1.3 × 10−17 s−1. The eastward decrease in upper-crustal shortening requires a progressive shift in crustal-thickening mechanisms across Qaidam basin, from dominantly upper-crustal shortening in the west to dominantly lower-crustal shortening in the east. Although sedimentation began synchronously at 65–50 Ma across the entire basin, the initiation ages of the southern and northern basin-bounding structures are significantly different; deformation started at 65–50 Ma in the north and at 29–24 Ma in the south. This information and the existing inference that the uplift of the Eastern Kunlun Range south of Qaidam basin began after 30–20 Ma imply that the Paleogene (65–24 Ma) Qaidam and Hoh Xil basins on both sides of the Eastern Kunlun Range may have been parts of a single topographic depression, >500 km wide in the north-south direction between the Qilian Shan and Fenghuo Shan thrust belts in the north and south. The development of this large Paleogene basin in central Tibet and its subsequent destruction and partitioning by the Neogene uplift of the Eastern Kunlun Range requires a highly irregular sequence of deformation, possibly controlled by preexist-ing weakness in the Tibetan lithosphere.