There is a magmatic lull period in the East Kunlun orogen (EKO) during the Jurassic to the Cretaceous. However, due to the lack of records of magmatic activity restricts our understanding of the late Mesozoic magmatic-tectonic evolution of the EKO. Herein, an integrated study of geochronology, whole-rock geochemistry and Sr-Nd isotopes were conducted for the Cretaceous mafic dykes in the EKO, Northern Tibet Plateau, to reveal their petrogenesis and geodynamic implications. LA-ICP-MS Zircon U-Pb dating reveals that the studied mafic dykes comprising diabase and diabase porphyry emplaced at ca. 80.9 ± 0.8 Ma. The Cretaceous mafic dykes have low contents of SiO2 (46.36 wt.%~47.40 wt.%) but high contents of MgO (6.79 wt.%~7.38 wt.%), TiO2 (1.91 wt.%~2.13 wt.%), Nb (12.4~18.3 ppm) and Nb/U ratio (31~39), resembling Nb-enriched mafic dykes. They exhibit chondrite-normalized rare earth element (REE) and primitive mantle-normalized trace element patterns, remarkably similar but not identical to the oceanic island basalts (OIB). The moderate REE fractionation ((La/Yb)N = 3.55~5.37), weak negative Eu anomalies (δEu = 0.87~0.97) and relative enrichment of Rb, Ba, K, as well as high contents of Cr and Ni and slightly depleted Sr-Nd isotopes (εNd(t) = −0.18~1.33), suggest that the studied dykes originate from a partial melting of spinel lherzolite and a little of garnet which was previously modified by subducted sediments. Combined with other evidence, we propose that the studied Cretaceous Nb-enriched mafic dykes in the Northern Tibet Plateau were formed in the intraplate setting, which may be a partial melting of the enriched mantle in the lower lithosphere caused by the activity of the East Kunlun strike-slip fault.