The discovery of an Ordovician supergiant, karst-type oil field in the North Tarim uplift, northwestern China, has triggered interest in hydrocarbon exploration in deeply buried paleouplifts. For multiphase uplift, a comprehensive understanding of large-scale, karst reservoir distribution requires knowledge of structural evolution from a three-dimensional perspective and its influence on karstification. High-resolution seismic and borehole data reveal that the North Tarim uplift can be subdivided into four segments from west to east. These segments exhibit along-strike variations in geological architecture, deformational magnitude, and eroded thickness. The evolution of this paleouplift is characterized by differential uplift of the various segments corresponding to the growth and linkage of multisegment faults and folds. Notably, the early Paleozoic tectono-stratigraphic evolution within the Southern slope is characterized by the transformation of a southwest-dipping monocline into two independent structural highs, implying significant tectonic relief evolution. Karst reservoirs, as targets of recent exploration, are characterized by various types of pore spaces and different degrees of karstification, and are distributed in different locations. The presence of a tectonic uplift significantly affects the distribution of karst units, indicating a spatial–temporal correlation between tectonic relief evolution and karstification. Tectonic relief evolution explains the superimposition of multiple types and stages of karstification at a single location. The improved karst evolution model that considers multiphase uplift can better interpret the superimposition of various genetic types of karst reservoirs, thereby providing theoretical guidance for karst reservoir prediction and future exploration in deep-marine basins associated with multiphase paleouplifts.