The Karakoram fault is an important strike-slip boundary for accommodating deformation following the India-Asia collision. However, whether the deformation is confined to the crust or whether it extends into the mantle remains highly debated. Here, we show that the Karakoram fault is overwhelmingly dominated by crustal degassing related to a 4 He-and CO 2rich fluid reservoir [e.g., He contents up to ~1.0−1.6 vol.%; 3 He/ 4 He = 0.029 ± 0.016 R A (1σ, n = 50); CO 2 /N 2 up to 3.7−57.8]. Crustal-scale active deformation driven by strike-slip faulting could mobilize 4 He and CO 2 from the fault zone rocks, which subsequently accumulate in the hydrothermal system. The Karakoram fault may have limited fluid connections to the mantle, and if any, the accumulated crustal fluids would efficiently dilute the uprising mantle fluids. In both cases, crustal deformation is evidently the first-order response to strike-slip faulting.