Abstract: The southwestern Tarim Basin experienced a complex construction and transformation process during the Paleozoic era. The unclear understanding of the superimposed transformation processes of the paleo-uplifts has restricted its oil and gas exploration. To address this issue, a series of studies, including seismic interpretation and structural analysis, were carried out based on the latest seismic and drilling data. The variation process of denudation was restored in different layers and periods, and the formation and transformation processes of the Hetian paleo-uplift were characterized. Based on the analysis of the ages and formation environments of basin-margin igneous rocks, the dynamic mechanism of the evolution and transformation of the paleo-uplift was discussed. Combined with the oil and gas exploration results, the controlling effects of the superimposed transformation of the paleo-uplifts were discussed. The results indicated that: (1) The denudation center in the southwestern Tarim Basin has undergone significant migration. During stage Ⅰ of the middle Caledonian period, denudation was confined to the southwestern margin of the basin. By stage Ⅲ of the middle Caledonian period, the denudation area expanded northward. During the early Hercynian period, the denudation center migrated eastward. In the late Hercynian period, it was located in the northwestern part of the basin. During the Himalayan period, the denudation center was located in the area where the present Bachu Uplift is situated. (2) The Hetian paleo-uplift exhibited a two-stage evolutionary pattern. It was an uplift along continental margins during stage Ⅲ of the middle Caledonian period and then transformed into an intracontinental uplift during the early Hercynian period. The Hetian paleo-uplift was mainly affected by the transformation of the western Maigaiti paleo-uplift in the northwestern margin of the Tarim Basin and the Bachu Uplift in the central basin, which adjusted the early paleogeomorphology of the Hetian paleo-uplift. (3) The migration and evolution of the paleo-uplift and the superimposed transformation between different paleo-uplifts controlled the distribution of different reservoir and caprock assemblages. The structural hinge zones between the Hetian, the western Maigaiti, and the Bachu paleo-uplifts were identified as favorable areas for oil and gas accumulation and should be the focus of future exploration efforts.