The Qaidam Basin is the largest sedimentary basin within the Tibetan Plateau, with up to ∼15-km-thick deposits accumulated in the Cenozoic. Understanding how it deformed in response to the far-field effects of India-Eurasia collision is critical to improving our knowledge of the mechanism underlying northward plateau growth. Unlike typical compressional basins, where upper-crustal deformation concentrates at their margins, the Qaidam Basin features the development of many NW- to WNW-striking folds across the entire basin. Why crustal shortening occurred in the interior of Qaidam Basin, ∼100 km away from the margins, together with the underground geometries beneath these folds, remains unknown. Herein, based on newly acquired three- and two-dimensional (3-D and 2-D) seismic reflection data, borehole logging, and scaled physical analog modeling, we investigated the geometries, kinematics, and formation mechanisms of the folds within the interior of Qaidam Basin. For the first time, we reveal three local weak layers in the Lulehe, Upper Xiaganchaigou, and Shangyoushashan Formations, respectively. They consist mainly of mudstone intercalated with evaporites and limestones, and they have different spatial distributions that are likely confined by major faults and folds. These mechanically weak layers became locally thickened or thinned in response to tectonic loading and/or facilitated detachment slip to form many décollement folds that were observed at the surface. The shallow deformation above the weak layers is largely decoupled from underlying basement-involved faulting and folding, which mostly terminate upward in these weak layers. Analog modeling results suggest that the lowermost and widely distributed décollement layer in the Lulehe Formation likely facilitated long-distance rapid propagation of deformation into the basin interior. In sum, our study highlights the significance of multiple weak layers during Cenozoic deformation in the Qaidam Basin interior.