A new methodology for improving the operational efficiency of ethylene cracking integrated with refining is proposed. In this work, ethylene feedstock optimization was achieved by screening the low-value materials and naphtha in the refinery through the molecular management approach. The process synthesis-intensification model for ethylene production was developed to identify the opportunities for improving operational efficiency. The P-graph method was applied to accelerate problem solving and generate process routes with the objective function of economic gross potential. To determine the optimal process route, the comprehensive operational efficiency index and light hydrocarbon feedstock ratio were further constructed for process route evaluation. A case study of a real ethylene-refining integrated complex indicates that the proposed method could effectively optimize the operational efficiency of ethylene production and that the economic and inherent safety performances could be notably increased by 22.34% and 67.81%, respectively.