The high-level sub-circular North Tihimatine granitic pluton, intrusive in the In Ouzzal terrane, has been dated at 600 ± 5 Ma (LA-ICP-MS U–Pb zircon) and at 602 ± 4 Ma (SHRIMP U–Pb zircon). At this time, while Tihimatine intruded a brittle In Ouzzal without major metamorphism, large high-K calc-alkaline granitoid batholiths emplaced in the adjacent terranes under ductile conditions and regional amphibolite facies metamorphism. Outside In Ouzzal, high-level plutons emplaced under brittle conditions are known only at c. 580 Ma. The In Ouzzal terrane (500 km × 80 to 5 km), made of c. 2 Ga very high-temperature granulitic lithologies with Archean protoliths, is the sole terrane within the Tuareg Shield to have been largely unaffected by the Pan-African orogeny. The field, petrographic, geochemical and isotopic characteristics of the In Ouzzal granitic plutons studied herein, give keys for the understanding of the atypical behavior of the In Ouzzal terrane. The In Ouzzal Pan-African granitoids present chemical compositions varying from medium-K to high-K calc-alkaline to alkaline compositions. This is recorded by the Sr and Nd radiogenic isotopes (−4 < ɛNd < −30; 0.704 < ISr < 0.713), pointing to a mixing between a heterogeneous and old Rb-depleted source, the Eburnean granulitic In Ouzzal crust, and a Pan-African mantle. The latter is represented by the nearby bimodal Tin Zebane dyke swarm (ɛNd = +6.2, ISr = 0.7028; Hadj Kaddour et al. in Lithos 45:223–243, 1998), emplaced along the mega-shear zone bounding the In Ouzzal terrane to the west. Trace element composition and Sr–Nd isotope modeling indicate that 20–40% of different crustal lithologies outcropping in the In Ouzzal terrane mixed with mantle melts. At least two, most probably three, Eburnean granulitic reservoirs with Archean protoliths are needed to explain the chemical variability of the In Ouzzal plutons. The Pan-African post-collisional period is related to a northward tectonic escape of the Tuareg terranes, including the rigid In Ouzzal terrane, bounded by major shear zones. Blocking of the movement of the In Ouzzal terrane, which occurred 20 Ma earlier (at 600 Ma) on the western side than on the eastern side, induced its fracturing along oblique faults inside the terrane. This process allowed asthenosphere to rise and to locally melt the In Ouzzal crust, giving rise to the studied plutons. This corresponds to a metacratonization process. The In Ouzzal terrane demonstrates that a relatively small rigid block can survive within a major orogen affected by a post-collisional tectonic escape at the cost of a metacratonization, particularly at depth along faults.