South China is famous for the extensive magmatism and polymetallic mineralization that took place there in the Mesozoic. Shilu is a large porphyry–skarn Cu–Mo deposit in the Yangchun Basin, South China. The lithology of the Shilu intrusion is granodiorite and quartz diorite, both of which are high-K calc-alkaline series, with high Sr (>400 ppm) content along with low Y and Yb contents. Most of the samples have characteristics of adakite except for a few samples that have slightly higher Y and Yb contents, which may be plausibly explained by crustal contamination. Laser Ablation Inductively Coupled Plasma Mass Spectrometry zircon U–Pb dating revealed ages between 106.6 ± 1.3 and 103.9 ± 0.5 Ma, with multiple magmatic pulses. Molybdenite Re–Os isochron age of 102.2 ± 2.9 Ma (MSWD = 9.4) was determined, which is identical to the youngest zircon U–Pb age (103.9 ± 0.5 Ma) within error. The Shilu intrusion has high oxygen fugacity as indicated by high zircon Ce⁴⁺/Ce³⁺ and Eu_N/Eu_N* ratios. Considering the geochemical characteristics (high Sr, and low Y and Yb contents), high oxygen fugacity, and copper mineralization of the Shilu intrusion, it was most likely formed by partial melting of a subducted young oceanic slab. Whole-rock Sr–Nd isotope-, zircon Hf isotope-, and whole-rock trace element analyses show that Shilu adakitic magmas may have interacted with type II enriched mantle and/or crustal materials during ascent. South China was affected by the Pacific tectonic regime to the east and the Neo-Tethys tectonic regime to the south in the Cretaceous. Based on the Pacific Plate drifting and rotation history, it is hard to explain how the Pacific Plate would have subducted and melted, forming adakitic rocks in the Shilu region. Considering the tectonic history of Southeast Asia and the South China Sea, the Neo-Tethys trench should have been much closer to the South China Block in the Cretaceous, and thus have had a greater impact on the South China Block. Based on the subduction direction, time of subduction, and distance between the Neo-Tethys subduction zone and the Shilu deposit, subduction of the Neo-Tethys ridge is the best mechanism for explaining the Shilu adakitic rocks and Cu–Mo mineralization.