Ethylene oxide (EO) is an important chemical intermediate for the production of various chemical products. The manufacturing of EO involves critical exothermic reactions at high temperature and high pressure, whose failure may cause catastrophic personal injury, severe air pollution, and tremendous economic loss. Thus, an EO plant must be well controlled under various situations, especially during its start-up operations. In this paper, a general methodology for improving chemical plant start-up operations through plant-wide dynamic simulation has been developed. It undergoes modeling and validations for steady-state, dynamic, and historian start-up operations. On the basis of the validated dynamic simulation model, the original plant start-up strategy is further examined and optimized to speed-up the plant start-up operation with enhanced safety considerations. A case study on an EO plant start-up has demonstrated the significant operational and economic benefits of the proposed methodology.