The pressing demand for clean water worldwide has increased attention to developing innovative desalination processes. In this work, the second law of thermodynamics is used to examine and assess two coupled desalination systems: a separation-based reverse osmosis (RO) system and a thermal desalination-based humidification–dehumidification (HDH) system. The HDH unit configuration used here is based on the working principle of the heat pump, where the process is open-air, open-water, and air-heated. The RO system is equipped with a pressure exchanger (PX) and has been examined under various operating circumstances, such as different feed water pressures, salinities, and flow rates. To improve the system’s sustainability, a solar photovoltaic system (PV) was integrated. An exergy model was used to precisely evaluate the system components and the hybrid systems by employing a proper exergy efficiency definition. The evaluation of the second law of thermodynamics for the RO–HDH–PX and RO–HDH–PX–PV systems indicated maximum efficiencies of 23% and 23.25%, respectively. A cost analysis was also performed on the hybrid RO–HDH–PX–PV desalination system using two approaches: the first included a battery storage system, whereas, in the second, the battery was not considered. When a battery storage system is included, the cost per cubic meter varies from USD 3.22 to USD 5.10. In contrast, it varies from USD 3.96 to USD 7.12 without a battery storage system.