Fuel assembly is located in the reactor core, which is the key component of nuclear power plant reactor. Its structural integrity will directly affect the safety and reliability of nuclear reactor operation. Fretting wear between fuel rod and grid supports caused by flow induced vibration is currently one of the main causes of fuel rod failure, which is also the most concerned phenomenon in fuel assembly design. Based on the random vibration theory and considering the interaction between fuel rod and support grid, a theoretical model and evaluation criteria for response prediction are proposed for the three possible flow induced vibration mechanisms in Pressurized Water Reactor (PWR) fuel assemblies, namely, turbulent excitation, fluidelastic instability and vortex shedding. At the same time, based on the Archard’s equation, the fretting wear analysis model of fuel rods is established, which is suitable for industrial application. The effects of transverse velocity, axial velocity and fluid density on the response of flow induced vibration and fretting wear of fuel rods are studied. The results show that the amplitude/wear depth varies with the transverse velocity in a quadratic way, exponentially with the axial velocity, and linearly with the fluid density. The established analysis process and evaluation method can provide technical support for the design and optimization of fuel assembly.