Our inability to determine the growth history and growth mechanism of the Tibetan plateau may be attributed in part to the lack of detailed geologic information over remote and often inaccessible central Tibet, where the Eastern Kunlun Range and Qaidam basin stand out as the dominant tectonic features. The contact between the two exhibits the largest and most extensive topographic relief exceeding 2 km across their boundary inside the plateau. Thus, determining their structural relationship has important implications for unraveling the formation mechanism of the whole Tibetan plateau. To address this issue, we conducted field mapping and analysis of subsurface and satellite data across the Qimen Tagh Mountains, part of the western segment of the Eastern Kunlun Range, and the Yousha Shan uplift in southwestern Qaidam basin. Our work suggests that the western Eastern Kunlun Range is dominated by south-directed thrusts that carry the low-elevation Qaidam basin over the high-elevation Eastern Kunlun Range. Cenozoic contraction in the region initiated in the late Oligocene and early Miocene (28–24 Ma) and has accommodated at least 48% upper-crustal shortening (i.e., ∼150 km shortening) since that time. In order to explain both the high elevation of the Eastern Kunlun Range and the dominant south-directed thrusts across the range, we propose that the Cenozoic uplift of the range has been accommodated by large-scale wedge tectonics that simultaneously absorb southward subduction of Qaidam lower crust below and southward obduction of Qaidam upper crust above the Eastern Kunlun crust. In the context of this model, the amount of Qaidam lower-crust subduction should be equal to or larger than the amount of shortening across Qaidam upper crust in the north-tapering thrust wedge system, thus implying at least 150 km of Qaidam lower-crust subduction since the late Oligocene and early Miocene. The late Oligocene initiation of contraction along the southern margin of Qaidam basin is significantly younger than that for the northern basin margin in the Paleocene to early Eocene between 65 and 50 Ma. This temporal pattern of deformation indicates that the construction of the Tibetan plateau is not a simple process of northward migration of its northern deformation fronts. Instead, significant shortening has occurred in the plateau interior after the plateau margins were firmly established at or close to their current positions. If Cenozoic crustal deformation across the Eastern Kunlun and Qaidam regions was accommodated by pure-shear deformation, our observed >48% upper-crustal shortening strain is sufficient to explain the current elevation and crustal thickness of the region. However, if the deformation between the upper and lower crust was decoupled during the Cenozoic Indo-Asian collision, lower-crustal flow or thermal events in the mantle could be additional causes of plateau uplift across the Eastern Kunlun Range and Qaidam basin.