Continental collision and subsequent slab break-off can induce granitoid magmatism of variable compositions and ages. We present new geochronological and geochemical data from granitoids in the eastern part of the West Kunlun Orogen, situated along the northwestern margin of the Tibetan Plateau. Our data reveal a distinct Late Ordovician–middle Silurian (450–428 Ma) magmatic flare-up event after closure of the Proto-Tethys Ocean (Proto-Kunlun Ocean) and following continental collision. Some high-Sr/Y granitoids show variable whole-rock (87Sr/86Sr)i, εNd(t), (206Pb/204Pb)t, and zircon εHf(t) values, indicating that these rocks were derived from heterogeneous sources comprising both juvenile and older material from the lower crust under amphibolite-facies conditions. We identify a linear spatial distribution of small-scale and short-lived magmatism and magmatic diversity (A-/S-/I-type) along the suture zone, and suggest that this Late Ordovician–middle Silurian magmatism in the West Kunlun Orogen was associated with slab break-off of the Proto-Tethys oceanic plate. The results improve our understanding of the closure of the Proto-Tethys Ocean, crustal growth, and the final formation of Gondwana in the NW Tibetan Plateau region.