The Qaidam Basin, located in the northern margin of the Qinghai–Tibet Plateau, is a large Mesozoic–Cenozoic basin, and bears huge thick Cenozoic strata. The geologic events of the Indian-Eurasian plate–plate collision since ~55 Ma have been well recorded. Based on the latest progress in high-resolution stratigraphy, a technique of balanced section was applied to six pieces of northeast–southwest geologic seismic profiles in the central and eastern of the Qaidam Basin to reconstruct the crustal shortening deformation history during the Cenozoic collision. The results show that the Qaidam Basin began to shorten deformation nearly synchronous to the early collision, manifesting as a weak compression, the deformation increased significantly during the Middle and Late Eocene, and then weakened slightly and began to accelerate rapidly since the Late Miocene, especially since the Quaternary, reflecting this powerful compressional deformation and rapid uplift of the northern Tibetan Plateau around the Qaidam Basin.