Organic Rankine Cycle (ORC) is a highly promising technology for converting heat to power, which has a widespread application in renewable energy utilization and waste heat recovery. Zeotropic working fluids are widely investigated to enhance the performance of ORC. In the present study, an experimental study on zeotropic mixture R1234ze(E)/R245fa is conducted under specified operating conditions and the operating behaviors of the ORC system are evaluated. An ORC simulation model (BP-ORC) based on a back propagation neural network and heat exchanger simulation modules is developed. The contribution factors that trigger the differences in heat transfer and system performance among the various working fluids are investigated. The operating behaviors of the heat exchangers and system are simulated for the working conditions beyond the experimental study. R1234ze(E)/R245fa (0.25:0.75 and 0.50:0.50) features a wider operating range of mass flowrate than R245fa due to their relatively lower density. The net power output of R1234ze(E)/R245fa (0.50:0.50) is 4.63 % higher than that of R245fa at a mass flow rate of 0.164 kg/s due to its relatively higher heat transfer performance. The variation of density and operating pressure plays a significant role in influencing the heat transfer behaviors and system performances.