The integration of power plants and desalination systems has attracted increasing attention over the past few years as an effective solution to tackle sustainable development and climate change issues. In this light, this paper introduces a novel modelling and optimization approach for a combined-cycle power plant (CCPP) integrated with reverse osmosis (RO) and multi-effect distillation (MED) desalination systems. The integrated CCPP and RO–MED desalination system is thermodynamically modelled utilizing MATLAB and EES software environments, and the results are validated via Thermoflex software simulations. Comprehensive energy, exergic, exergoeconomic, and exergoenvironmental (4E) analyses are performed to assess the performance of the integrated system. Furthermore, a new multi-objective water cycle algorithm (MOWCA) is implemented to optimize the main performance parameters of the integrated system. Finally, a real-world case study is performed based on Iran's Shahid Salimi Neka power plant. The results reveal that the system exergy efficiency is increased from 8.4 to 51.1% through the proposed MOWCA approach, and the energy and freshwater costs are reduced by 8.4% and 29.4%, respectively. The latter results correspond to an environmental impact reduction of 14.2% and 33.5%. Hence, the objective functions are improved from all exergic, exergoeconomic, and exergoenvironmental perspectives, proving the approach to be a valuable tool towards implementing more sustainable combined power plants and desalination systems.