Nuclear power is well established and developed all around the world, and cooling water is widely taken from the sea as the ultimate heat sink in most coastal nuclear power plants. However, marine organisms and debris blockage events of cooling water intake structures occur frequently at nuclear power facilities worldwide due to the adverse effect and challenges of global climate change, posing severe risks to nuclear safety and cost-effectiveness. In this paper, the effect of climate variability on cooling water systems of nuclear power plants has been discussed and analyzed in detail. Based on the design and engineering experience of some nuclear power plants in operation against marine organisms and debris blockage events, a series of technical strategies and good practices have been proposed towards blockage prevention and hazard elimination for nuclear operators, aimed at improving the safety of cooling water systems, ensuring energy sustainability and meanwhile establishing an environmentally friendly defense system under the context of global climate change.