The Handan-Xingtai district is located in the western margin of the eastern North China Craton (NCC). It is one of the largest concentrations of iron skarn deposits in China. In the past decades, numerous Mesozoic intermediate-felsic intrusions were reported in this area. However, the genetic relationship between the Mesozoic intrusions and iron mineralization still remain controversial. Here we present mineral compositions, major and trace elements, as well as Sr–Nd isotopic data of both the ore-bearing and ore-barren intrusive complexes. Most of the amphiboles from the ore-bearing complexes are magnesiohastingsites with a small part of them being edenites, whereas those from the ore-barren one are mostly ferropargasites and pargasites. All biotites from the studied complexes are magnesio-biotites. Mineral thermometer and oxybarometry show that the magma of ore-bearing intrusive complexes has lower temperatures but higher oxygen fugacity than those of the ore-barren ones. In addition, all the studied complexes show enrichment in light rare earth elements (LREE) and depletion in heavy rare earth elements (HREE) and high field strength elements (HFSE), with high Sr/Y ratios and insignificant Eu anomalies, similar to adakitic rocks. However, samples from the ore-barren one have obviously higher εNd(t) values (−11.2 to −7.2) than those of ore-bearing ones (εNd(t) = −18.2 to −12.3). Our new results demonstrate that the ore-bearing and ore-barren complexes cannot be genetically related, but evolved via discrete magmatic events. We propose that the ore-bearing complexes were derived from a mixed source, which consists of enriched lithospheric mantle and ancient lower continental crust, whereas the ore-barren one was generated by partial melting of an enriched lithospheric mantle. The major difference between the ore-bearing and ore-barren complexes is involvement of the continental lower crust, which has a greater contribution to the iron mineralization. The magmatism and metallogeny in the Handan-Xingtai district were a result of the extensive craton destruction and lithospheric thinning in the eastern part of the NCC.