The Eastern European Alps formed during two orogenic cycles, which took place in the Cretaceous and Cenozoic, respectively. In the Ötztal-Stubai Complex—a thrust sheet of Variscan basement and Permo-Mesozoic cover rocks—the record of the first (Eoalpine) orogeny is well preserved because during the second (Alpine) orogeny, the complex remained largely undeformed. Here, new zircon (U–Th)/He (ZHe) ages are presented, and thermokinematic modeling is applied to decipher the cooling and exhumation histories of the central part of the Ötztal-Stubai Complex since the Late Cretaceous. The ZHe ages from two elevation profiles increase over a vertical distance of 1500 m from 56 ± 3 to 69 ± 3 Ma (Stubaital) and from 50 ± 2 to 71 ± 4 Ma (Kaunertal), respectively. These ZHe ages and a few published zircon and apatite fission track ages were used for inverse thermokinematic modeling. The modeling results show that the age data are well reproduced with a three-phase exhumation history. The first phase with relatively fast exhumation (~250 m/Myr) during the Late Cretaceous ended at ~70 Ma and is interpreted to reflect the erosion of the Eoalpine mountain belt. As Late Cretaceous normal faults occur at the margins of the Ötztal-Stubai Complex, normal faulting may have also contributed to the exhumation of the study area. Subsequently, a long period with slow exhumation (<10 m/Myr) prevailed until ~16 Ma. This long-lasting phase of slow exhumation suggests a rather low topography with little relief in the Ötztal-Stubai Complex until the mid-Miocene, even though the Alpine orogeny had already begun in the Eocene with the subduction of the European continental margin. Accelerated exhumation since the mid-Miocene (~230 m/Myr) is interpreted to reflect the erosion of the mountain belt due to the development of high topography in front of the Adriatic indenter and repeated glaciations during the Quaternary.