In a complex environment, large bridges will present different adhesion coefficient, often accompanied by large crosswind, which makes the flow field around the vehicle complex and changeable. It is easy to cause unnecessary lane change and sideslip of the vehicle, which will affect the driving stability and lead to serious traffic accidents. Therefore, this paper studies the aerodynamic stability of cars passing through the bridge tower at high speed under different road adhesion and crosswind conditions. The detached-eddy simulation (DES) model was employed and the reliability of the DES model was verified by wind tunnel tests. An overlapping mesh technique was adopted to realize the motion of the vehicle. A multibody dynamic (MBD) model of the vehicle was established, and its robustness was verified. A two-way coupling model was then established based on the aerodynamic and MBD models. Subsequently, the aerodynamic characteristics and dynamic response of the vehicle passing through the bridge tower at a high speed were compared and analyzed using one-way and two-way coupling methods, with road adhesion coefficients of 1.0, 0.6, and 0.4 under crosswind conditions. The results show that the aerodynamic characteristics of the vehicle passing the bridge tower at a low adhesion coefficient under two-way coupling change evidently, and the trajectory and body attitude of the vehicle change significantly. As the adhesion coefficient of the road surface decreases, the vehicle passes through the bridge tower with a large lateral displacement and yaw angle. The maximum lateral force of −1406 N and the maximum yaw moment of 803 N∙m are generated when the car passes through the bridge tower under the two-way coupling with the adhesion coefficient of 0.4. Under two-way coupling, the lateral displacement and yaw angle caused by the bridge deck with an adhesion coefficient of 0.4 are 0.265 m and 0.0205 rad, respectively, which is larger than those of the bridge deck with adhesion coefficients of 1.0 and 0.6. Because the coupling effect of aerodynamic and vehicle motion is not considered in the one-way coupling, the one-way and two-way coupling simulation results differ significantly. The results indicate that it is necessary to use a two-way coupling method to study the aerodynamic stability of vehicles passing through a bridge tower at a high speed under crosswind conditions.