This paper evaluated the performance of a proton exchange membrane fuel cell using multiple criteria, including thermodynamic, economic, and degradation aspects. The electric current, temperature, and hydrogen/oxygen pressures are the process parameters for evaluating the degradation rate, total costs, electrical efficiency, and cell power. The non-dominated sorted genetic algorithm-II (NSGA-II) optimized the system based on evaluation index improvement to reach the three-dimensional Pareto solution and the optimal operation parameter set. Low current and high hydrogen/oxygen pressure benefit the reduced degradation rate, decreased total costs, and improved electrical efficiency. Specifically, the optimized cell's degradation rate and total costs are reduced by 47.67% and 31.26%, respectively, compared with the control, unoptimized cell. The electrical efficiency at the optimal point is 44.29%, 11.14% higher than the control. Moreover, the total electrical power over a lifetime has increased due to the extended useful life.