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Thermotectonic modeling was performed for the crystalline rocks of South Tuva using the apatite fission-track analysis. Thermotectonic modeling made it possible to visualize the Late Mesozoic and Cenozoic cooling history of the Pre-Mesozoic basement rocks, and to reconstruct the chronology and scale of the denudational processes over the last 125 myr and the evolution of paleorelief of South Tuva over the last 100 myr. The modeling results depicted several Mesozoic-Cenozoic episodes of cooling due to differential denudation and exhumation of the Pre-Mesozoic basement rocks. A differential denudation is related to an asynchronous activation of fault structures controlling the tectonic evolution of South Tuva. It is shown that the Early Cretaceous (~125–100 Ma) activation of the Agar-Dag-Oka thrust fault zone could result from the post-collisional processes after the collision between Siberia and Amuria and/or consecutive collision between the Cimmerian blocks. An intense activation of the Agar-Dag-Oka fault zone in the Late Cretaceous (~100–75 Ma), accompanied by significant basement rock exhumation in the eastern South Tuva to absolute heights of 1200 m, could be caused by the Karakoram-Pamir collision in the south of Eurasia. The Late Cenozoic (25–0 Ma) activation of the main fault zones of South Tuva represents a far-field effect of the Indo-European collision on the southern Eurasian continent. At the same time, there were the maximum basement uplift in the junction zone between the South Tannuola and Ubsunur-Bii-Khem fault zones and the transformation of relief of South Tuva from moderately dissected, with absolute heights of 500 to 1400 m, to modern, with absolute heights of 800 to 2600 m.