The northern South China Sea (SCS) continental margin was proposed to be an active margin during the Mesozoic. However, only a few papers discussed the Mesozoic structural evolution in this region. Here, we provide information based on the seismic profile interpretations with age control from biostratigraphic studies and detrital zircon U-Pb dates of well MZ-1-1 in the western Dongsha-Penghu Uplift of the northern SCS continental margin. The industrial seismic profiles reveal evidence for structural inversion as represented by folds and high-angle reverse faults, formed by reactivation of pre-existing normal faults. The inversion event likely started after the Early Cretaceous, and developed in Late Cretaceous, but ceased before the Cenozoic. The areal extent of the structural inversion was restricted in the western Dongsha-Penghu Uplift and was approximately 100 km in width. Based on the paleogeographic reconstruction of SCS, the structural inversion was likely formed by a collision between the seamount (volcanic islands) swarm of the current North Palawan block (mainly the Calamian Islands) and the northern SCS continental margin around Late Cretaceous.