Thrusting implication in the crustal thickening history of eastern Tibet is highly debated. The ∼250 km‐long Muli thrust of the Yalong thrust belt in SE Tibet is a major Miocene structure with a pronounced topographic step (∼2,000 m). Using thermo‐kinematic modeling based on thermochronology data, we constrain the crustal geometry of the thrust as being steep (>70°) at the surface, in agreement with field observations, and flattening at depth (≥20 km) on an intra‐crustal décollement. Thrusting motion on the fault shows a velocity of 0.2 ± 0.06 km/Ma since 50 Ma, followed by an acceleration at a rate of 0.6 ± 0.08 km/Ma starting at 12.5 ± 1 Ma, yielding a total of ∼15 km of exhumed crust. Deeper, deformation may be localized through a ductile shear zone, and be related to the ∼15 km Moho step and shear wave velocity contrast imaged by tomography beneath the Yalong thrust belt. Plain Language Summary The India‐Eurasia collision (∼50 million years ago Ma) led to the formation of the Tibetan Plateau, the world's largest and highest orogenic plateau. The formation and evolution of such a unique geological feature has been one of the main controversies in Earth Sciences for decades, especially regarding the role of faulting in the thickening of the crust. Here, we present 3D thermo‐kinematic models of thermochronology data allowing to constrain the exhumation history of the Muli thrust fault, a ∼250 km‐long major structure of the SE Tibetan margin, linked to significant steps in surface topography and in crustal boundary at depth (Moho). We constrain a steep fault (>70°) within the upper crust, consistent with field observations, that flattens at depth (≥20 km). The Muli thrust presents rapid thrusting motion (0.6 ± 0.08 km/Ma) that initiated at ∼12.5 Ma, following a slower phase (0.2 ± 0.06 km/Ma) since 50 Ma, with total rock exhumation of ∼15 km. This underlines the important role of thrust faulting in the thickening of the SE Tibetan crust. Key Points Thermo‐kinematic modeling of Muli thrust, a major thrust fault of SE Tibetan Plateau 15 km crust exhumation in 50 Ma on a high‐angle (>70°) ramp—décollement fault linked to thickening of SE Tibetan crust Fault related to significant Moho step and shear wave velocity contrast in deep crust suggests entire crust implication