During the development of geothermal resources, thermal and non-uniform in-situ stresses can lead to wellbore integrity failures in geothermal wells. To evaluate the integrity of casing-cement-formation combination system under coupled thermal and non-uniform in-situ stress, an integrity evaluation mathematical model is established based on thermodynamics, elastodynamics, and the equivalent stress criterion. The performance of cement sheath mechanics and combination system sealing under different temperature conditions is investigated based on the designed experimental apparatus. By integrating numerical simulation and experimental approaches, a method to evaluate the integrity of the wellbore combination system in geothermal wells has been developed and the risk of temperature variations and non-uniform in-situ stresses on the casing, Cementing I and II interfaces has been analysed. Experimental results show significantly reduced mechanical and sealing performance under high temperature conditions. Numerical simulations indicate that the Cementing I and II interfaces, as well as the cement sheath, serve as weak points for potential integrity failure in geothermal wells, with Cementing I interface being particularly susceptible. The developed method can effectively evaluate the wellbore combination system integrity under the coupling effect of thermal stress and non-uniform in-situ stress, which is crucial for ensuring the wellbore integrity and safe development of geothermal energy.