Abstract: The complexity and diversity of fault systems in sedimentary basins, as well as their formation and evolution mechanisms, have long been of great concern. Taking the Zhusan Depression on the northern margin of the South China Sea as the research objective, based on the structural analysis of a large amount of three-dimensional seismic data, the transformation in the direction of the Cenozoic regional extension was analyzed, and its role of control on the development and evolution of fault systems was explored. Results indicate that the faults in the Zhusan Depression have the characteristics of multiple strikes, levels, and properties. In fault strike, they could be divided into three groups: NNE-NE, NWW-NW, and near EW. There are differences in the development characteristics, properties, and distribution patterns of faults in different strike directions. The regional extension direction of Zhusan Depression experienced clockwise rotation evolution in the Cenozoic, from the NW-SE direction of the Paleocene-Eocene Shenhu Wenchang Formation sedimentary period, to the nearly SN direction of the Oligocene-Early Miocene Enping-Zhujiang Formation sedimentary period, and to the Middle Miocene Hanjiang Formation sedimentary period in NNE-SSW direction. The transformation of the direction of regional extension in the Cenozoic and the preexisting faults jointly controlled the development and evolution of the Pearl River Delta fault system, resulting in differences in the characteristics of active faults in different stages of evolution. This is mainly manifested in the disappearance of the southern branch of the western segment of the southern fault zone, which was strongly active during the Paleocene-Eocene in the middle and late stages. The fault properties of different segments of the northern branch of the southern fault zone are different. For example, the bending of Qionghai No.1 Fault and structural inversion in the northern section of Wenchang B Sag, reflect the control effect of direction change of the Cenozoic regional extension on development and evolution of fault system in the Zhusan Depression.