The organic Rankine cycle-vapor compression refrigeration combined system is an effective way to sufficiently utilize low-grade heat energy and achieve refrigeration without electricity consumption. The combined system typically includes single-fluid configuration with a common condenser and double-fluid configuration with two condensers. In order to determine the optimal configuration of the combined system, the performance comparison of two system configurations using pure/mixture working fluids is carried out. The main innovations of this paper different from the previous literature are as follows: the performance comparison is based on the results of multi-objective optimization. Moreover, the working fluids are selected as the decision variables of multi-objective optimization. In order to provide theoretical guidance for the determination of the optimal system under different performance preferences, single-objective optimization is also conducted. The optimal system is determined under comprehensive performance and different performance preferences. The results indicate that the double-fluid system configuration has better thermodynamic performance than the single-fluid system configuration. Moreover, the performance of the systems using mixture working fluids is greatly improved compared with that of the system using pure working fluids. When users’ performance preference is coefficient of performance, system exergy efficiency or comprehensive performance, the optimal system is the double-fluid system using mixture working fluids with system coefficient of performance of 0.23, system exergy efficiency of 43%, and grey relational degree of 0.96, respectively. When users’ performance preference is levelized cost of cooling, the optimal system is the single-fluid system using mixture working fluids with levelized cost of cooling of 0.027$/kWh.