A combination of U-Pb zircon ages and geochemical and Sr-Nd-Hf isotopic data are presented for the Early Paleozoic granodiorites from the Haoquangou and Baimawa plutons in order to probe the crustal thickness variation of the eastern North Qilian and the diachronous evolution of the North Qilian orogen. The granodiorites formed at 436–435 Ma and have high Sr/Y ratios (63–117). Elemental and isotopic data combined with geochemical modeling and comparisons with experimental data suggest that they were produced from the melting of relatively juvenile mafic rocks in the thickened lower crust. Together with other petrological and geochemical data and the calculation of variation in crustal thickness, this indicates that the eastern North Qilian experienced clear crustal thickening and thinning from the Late Ordovician to Late Silurian. Based on available data, we suggest that diachronous collision from east to west, which probably resulted in the distinct intensity of orogenesis between eastern and western North Qilian, can well account for the differential distribution of Early Paleozoic high Sr/Y magmatism and other geological differences between the eastern and western parts of the North Qilian. Our study also implies that diachronous collision may lead to, apart from distinct metamorphic, structural and sedimentary responses, the large differences in magmatism and deep crustal processes along the orogenic strike.