An optimization design method based on field synergy principle is developed for Multi-stream plate-fin heat exchangers (MPHEs) with a segmented differential model. The heat exchanger is divided into a number of sub-exchangers along the main stream, and each sub-exchanger consists of N passages along the height of the exchanger. Compared with the traditional heat exchanger design, this method allows temperature and pressure fields to be obtained via coupling calculation with consideration of variable physical properties and the axial heat loss of the heat exchanger. Finally, the heat exchanger is optimally designed using a temperature-difference uniformity optimization factor based on field synergy principle. This design model can provide an accurate temperature field and pressure field, because the stream properties are determined by the mean temperature and pressure of each local sub-exchanger. Optimum results indicate that the temperature distribution on the cross section of the heat exchanger is relatively uniform and that the temperature difference of heat transfer for each stream is always a small value. These characteristics prove the feasibility and effectiveness of this design model. In this paper, a case of five stream plate-fin heat exchangers for an ethylene plant is designed under a practical cold box operating condition with the proposed model, the structure and heat transfer of which are optimally determined. The design model and optimization method proposed in this work can provide theoretical and technical support to the optimization design of MPHEs.