In recent years, incidents of jellyfish outbreaks invading cooling water system have occurred frequently in nuclear power plants, which directly affects the safe and stable operation of the units. In response, the prevention and control of disaster-causing jellyfish is aimed at increasing the response margin time and reducing the impact of invasion. It involves the application of multidisciplinary frontier achievements, and the design and construction of a complete prevention and control system should be based on the concept of defense in depth and systematic thinking. This paper summarizes these studies and practices, combined with the actual working conditions and needs of the nuclear power plant cooling water site, a interdisciplinary and systematic solution for the prevention and control of jellyfish in the whole chain covering the five defense lines of “prediction, monitoring, warning, interception and response” is proposed. Which is divided into the far-sea layer, offshore layer, nearshore layer, and shore layer according to the time and space elements and logical relationship to form a layered construction plan. It has the characteristics of modularization and intelligence, and can effectively improve the prevention and control of jellyfish disasters in nuclear power plants.