The refrigeration system is one of the most important and critical utility systems in the chemical and petrochemical industries. The traditional cascade refrigeration system (CRS) has been used for decades in ethylene plants. However, the mixed refrigerant system (MRS) with higher energy efficiency and less capital expenses than CRS has not widely been applied in ethylene plants. In this paper, a general methodology has been proposed for the synthesis of a tertiary refrigerant of MRS containing a mixture of methane, ethylene and propylene that can satisfy all the cooling/heating refrigeration that the traditional ethylene-propylene CRS serves in an ethylene plant. The exergy-temperature chart combined with the exergy analysis is presented to analyze comprehensively the thermodynamic nature of both CRS and MRS. Furthermore, the comparison of economic performances of these two different systems is also conducted. The efficacy of the developed MRS methodology has been demonstrated by a case study, where the capital and utility costs are respectively saved by 21.0% and 12.1%; and the compressor shaft work is also reduced by 11.2% compared with the CRS.