Long-span highway–railway double-deck truss bridges are mostly located in urban centers, where noise pollution and traffic safety issues have a great impact. The fully enclosed barrier has excellent sound insulation and windproof performance and has been widely used in double-deck truss bridges in recent years. However, the large volume and the low air permeability rate will affect the aerodynamic characteristics of the bridge, resulting in vortex-induced vibration (VIV). To analyze how the fully enclosed barrier influences the highway–railway bridge VIV performance, this study analyzes the Huangjuetuo Yangtze River Bridge, combined with the wind tunnel test and the numerical calculation method to study different variations of the static three-force coefficient, the change of VIV response, and its influence mechanism after setting the fully enclosed barrier. The results show that the static three-force coefficient of the double-deck truss bridge changes significantly, the drag coefficient increases, and the absolute values of the lift coefficient and the moment coefficient decrease after the fully enclosed barrier is set. The aerodynamic performance of the bridge is significantly reduced after the fully enclosed barrier is set, and the amplitude and range of the VIV response are increased. Vertical bending VIV increased by an average of 58.5%, and torsional VIV increased by an average of 21.9%. Considering driving comfort and safety, attention should be paid to the double-deck truss bridge with a fully enclosed barrier.