Abstract: In cooling down process, the cryogenic wind tunnel has a wide range of temperature variation, which may lead to strong structural thermal stress and affect equipment smooth and safe operation. The cryogenic wind tunnel diffuser section is investigated in this paper based on fluid-thermal-structural coupling. The data exchange interface for multiple physical fields, MpCCI, is adopted to combine the structural finite element software, Abaqus, and Computational Fluid Dynamics (CFD) software, Fluent. The fluid-thermal-structural coupling model of the diffuser section is established to investigate heat transfer characteristics of the cryogenic internal flow field and calculate the distribution of temperature and stress in the cryogenic wind tunnel structure. The cryogenic wind tunnel experiment indicates that the results of fluid-thermal-structural co-simulation agree well with the test results, which reflect correctly the thermodynamic characteristic of cryogenic wind tunnel structure and provide reliable analysis method for safety performance optimization of wind tunnel structure.