A large-scale parallel-unit seawater reverse osmosis desalination plant contains many reverse osmosis (RO) units. If the operating conditions change, these RO units will not work at the optimal design points which are computed before the plant is built. The operational optimization problem (OOP) of the plant is to find out a scheduling of operation to minimize the total running cost when the change happens. In this paper, the OOP is modelled as a mixed-integer nonlinear programming problem. A two-stage differential evolution algorithm is proposed to solve this OOP. Experimental results show that the proposed method is satisfactory in solution quality.