Yishu fault zone and Weibei depression controlled by Yishu fault zone are important research objects for revealing tectonic evolution and hydrocarbon accumulation mechanism. It is of crucial significance for deepening geological theories and guiding hydrocarbon exploration. Through integrating 3D seismic interpretation, reconstruction of structural equilibrium profiles, and geochemical analysis of source rocks, multistage activity characteristics of Yishu faault zone and the controlling role of Weibei depression on oil and gas have been revealled systematically. It is showed that the structural evolution process of Yishu fault zone is extremely complex. The evolution of Weibei depression has experienced four stages, they are sinistral strike slip, leftright rotation conversion, dextral strike slip, and regional depression. A unique structural pattern of northern fault depression and southern overlap ("northern fault southern overlap") have been formed. The tectonic activity dominates the sedimentary filling and oil and gas accumulation in the depression. The late stage uplift event of the fourth section of Shahejie formation led to the differentiation of the maturity of source rocks from east to west. A unidirectional fault transport system developed in the eastern Zaohu Duanbi belt. Lateral migration of hydrocarbons and the formation of a "singlestage accumulation enrichment" model has formed. The western region is affected by the superposition of multiple faults, exhibiting the characteristics of "two periods of accumulation near the source", and ultimately forming a distribution pattern of oil and gas resources with "rich in the east and poor in the west". It is identified that Zaohu Duanbi belt is an efficient exploration target area. It will not only provide theoretical support for oil and gas exploration, but also provide important scientific basis for improving the success rate of oil and gas exploration and regional resource development.