In this study, a thermodynamic model of a hybrid system consisting of a proton-exchange membrane fuel cell (PEMFC) system and an organic Rankine cycle (ORC) system is established using Aspen Plus software. The optimal working fluid is selected by comparing the performance of pure working fluids and zeotropic mixtures of working fluids in an ORC system. The zeotropic working fluid consisting of R245fa/R123 with a mixing ratio of 0.6/0.4 shows the best performance. The effects of some key parameters, including the current density and operating temperature, on the performance of the PEMFC–ORC system with zeotropic mixing fluids are discussed. The results indicate that the power and efficiency of the PEMFC–ORC system with the zeotropic mixing fluid increase with increasing operating temperature. When the R245fa/R123 zeotropic working fluid with a mixing ratio of 0.6/0.4 is used, the net power and efficiency of the hybrid system reach optimum values under the studied boundaries, with improvements of 12.87% and 4.84%, respectively. The influence of the maximum allowable evaporation pressure and stack operating temperature on the selection of optimum working fluid for the hybrid system is discussed in addition.