Large-span bridges often exhibit complex and variable flow fields around their bridge decks because of the coupling of natural and structural winds, which induce vortex-induced bridge vibrations, threatening the driving safety and comfort of vehicles. To capture the response characteristics of vehicles crossing bridges in this type of environment, a novel framework is proposed in this paper from aerodynamic and system dynamics perspectives for analyzing the dynamic responses and ride comfort of vehicles under the coupled effects of crosswinds and vortex-induced vibrations. The real driving behavior of a vehicle is simulated by establishing a 14-degree-of-freedom dynamic model, incorporating a driver preview controller, for the entire vehicle. Subsequently, a wind tunnel test and a numerical simulation are combined to measure the vortex-induced bridge vibrations and the aerodynamic loads imposed on the vehicle body, producing dynamic response parameters that are used to evaluate the driving stability and ride comfort of the vehicle under these disturbances. The results show that the proposed analytical framework effectively reproduces the driving characteristics of the vehicle under different levels of crosswinds and vortex-induced vibration excitations, accurately simulating the dynamic responses of the vehicle.