Here, to study wind-resistance performance of a split 3-box section main girder bridge and propose effective aerodynamic optimization measures, based on a long-span cable-stayed suspension bridge with split 3-box section main girder for the road-rail dual purpose, wind tunnel tests for segment models were conducted under different wind attack angles, different turbulence flow fields and five different aerodynamic measures. The results showed that box separation can greatly increase the flutter critical wind speed of main girder section, but this situation can complicate the flow field among 3 boxes to cause vortex-induced vibration (VIV); under conditions of the original section in completed bridge state with attack angles of 0° and ±3°, torsional VIV appears with the maximum torsional amplitude of 1.238°; in general, the flutter critical wind speed is higher than 97.3 m/s; the effects of three measures of bridge deck flow restrictor, different maintenance track positions and beam bottom flow deflector are not ideal for torsional VIV suppression; the longitudinal grid with uniform distribution at gap of boxes can effectively suppress torsional VIV, the smaller the air permeability, the more obvious the optimization effect; the grid with air permeability less than 23% can cause decrease in the flutter critical wind speed; the combination measure of grid with 10% air permeability and lower central stabilizer plate can completely suppress torsional VIV and ensure bridge flutter performance; based on the computational fluid dynamics (CFD), the flow field structure and aerodynamic force variation law around the original section and main girder with optimized conditions are obtained; the main cause of main girder’s VIV is the formation of large-scale vortices at gaps among boxes and above downstream highway box; after optimization, large-scale vortices are scattered at gaps among boxes, and root mean squares of lift force and torque time histories are obviously reduced to effectively improve VIV performance of main girder; at the same time, both slopes of lift force and torque coefficient curves under the optimized conditions are positive within the attack angle range of -5°—5°, so main girder has necessary conditions for aerodynamic stability.