In the western segment of the East Kunlun Orogen (WEKO), muscovite granite and garnet granite from the Hureguole intrusion exhibit zircon U-Pb ages of 435–442 Ma. Geochemically, these rocks contain high concentrations of SiO2, K2O and Al2O3, with low concentrations of TiO2 and MgO, indicating a peraluminous high-K calc-alkaline affinity. They are enriched in Rb, Th, U and LREE, depleted in Eu, Ba, Sr and Ti, being classified as S-type granites. Negative whole-rock εNd(t) values (?9.8 to ?9.1) and zircon εHf(t) values (?11.6 to ?8.2) for those granites indicate that they were derived from partial melting of pelitic rocks in the Paleoproterozoic Baishahe Formation of the Jinshuikou Group. Based on the collected zircon ages, Cambrian?Devonian magmatic activity in the WEKO was divided into three stages: early (446–520 Ma), middle (427–441 Ma) and late (372–424 Ma) stages. Statistically, whole-rock Nd and zircon Hf isotope data (εNd(t)/TDMNd, εHf(t)/TDMCHf) from Paleozoic igneous rocks in the WEKO reveal a magma source that was initially dominated by depleted mantle components in the northward subduction stage of the Proto-Tethyan Ocean plate (446–520 Ma), shifting to predominantly crustal sources during the closure period of the North Qimantagh back-arc basin (427–441 Ma), then to crust-mantle mixed sources in the post-collision stage (372–424 Ma).