Multi-hazard coupling accidents in chemical plants lead to a larger number of fatalities and property losses, seriously threatening the sustainable development of society. Therefore, this study conducted a comprehensive analysis on the evolution process of chemical multi-hazard coupling accidents using a computational fluid dynamics (CFD) code, which was used to simulate fireball, pool fire and toxic gas dispersion in chemical plants. The effect of safety barriers on the thermal radiation and toxic gas concentration was also investigated. The results show that the activation of safety barriers could cut off the accident chain, thus preventing the domino accidents. The hazardous areas caused by explosions and fires basically failed to change over time, while the hazardous areas caused by toxic gas dispersion expanded over time. Furthermore, on the basis of CFD results and the shortest path algorithm, we investigated the strategies for evacuation route optimization under different accident scenarios. It was found that the activation of safety barriers could ensure the normal passage of roads, thus reducing the total time consumed for evacuation. As the scope of the area polluted by accidents varied with time, the optimal evacuation route changed with the pre-evacuation time.