The Western Kunlun Orogenic Belt (WKOB), along the northwestern margin of the Qinghai–Xizang Plateau, was formed by the collision of Gondwana-derived terranes to the south and the Tarim Block to the north and was closely associated with closure of the Proto-Tethys Ocean during the late Neoproterozoic to early Paleozoic. We present a combined zircon UPb geochronology, whole-rock composition, and Sr–Nd–Hf isotopic study of syn-collisional granitoid plutons and mafic microgranular enclaves (MMEs) in the region. Zircon UPb dating yields ages of 443.8 ± 4.4, 451.9 ± 4.2, 462.9 ± 3.5, and 456 ± 4.2 Ma for the Tongayoupuagezi, Shanjie, and Pishigai plutons and MMEs from the Pishigai pluton, respectively. The granitoids are metaluminous to weakly peraluminous (A/CNK = 1.00–1.17) and belong to the high-K calc-alkaline series. They have (87Sr/86Sr)i ratios of 0.7058–0.7154, εNd(t) values of −8.78 to −0.93, and εHf(t) values of −19.72 to +6.87. The MMEs have variable SiO2 contents (45.7–60.2 wt%) and are more mafic than the host granitoids, but have similar Sr–Nd–Hf isotopic compositions to the host granitoids [(87Sr/86Sr)i = 0.7102–0.7110; εNd(t) = −6.57 to −3.56; εHf(t) = −7.17 to −1.81]. The MMEs are fragments of cumulates formed during the early stages of magma evolution. The granitoids were produced by the partial melting of a mélange source. The new data support the view that the Middle–Late Ordovician syn-collisional granitoids with MMEs distributed along the WKOB represent a magmatic response to terrane collision. This suggests that juvenile crustal growth in older orogenic systems, which occurs by arc addition, also involves some vertical addition during the final stage of orogenic collision. Our study suggests that mélange diaper melting is a key mechanism of crustal growth during the syn-collision stage in continental collision zones, associated with slab breakoff.