The selection of reasonable working fluid dramatically impacts the performance of the Organic Rankine Cycle system for the recovery of ship main engine waste heat. In this paper, the Organic Rankine Cycle system (ORC) was used to recover waste heat from the ship’s main engine of the 6G70MEC9.5-HPSCR ship (maximum power 21840KW): According to the engine room working environment requirement, the safety of the working fluid was given top priority. The selection principle of organic work gases was proposed, with the net output work of the system as the index, the system circulation thermal efficiency, and the target parameter (the ratio of the net output work of the system to the total area of the heat exchanger) as the reference. The thermodynamic analysis of the seven organic working fluids that meet the system’s conditions was carried out. The result indicates that as the main engine load increases, the net output work of the ORC system increases, and the cycle thermal efficiency decreases; the working fluid with high critical temperature has a high working ability and poor economy. In the evaporation pressure range of the seven organic working fluids, R365mfc with better work capacity is selected as the suitable circulating fluid for the system.