<p>This paper proposes a decoupling optimal control method based on feedforward compensator and reduced active disturbance rejection controller (RADRC) about multiple-input-multiple-output (MIMO) system with coupling and uncertain time delay. In MIMO system, the effect of coupling is evaluated by the relative gain array (RGA), based on which the appropriate control variables are selected. And by the feedforward compensator, MIMO system with interference and uncertain time delay are separated into individual Single–Input–Single–Output (SISO) systems. The novelty of this paper is first to decouple MIMO system into individual SISO systems by feedforward compensator, and then to design optimal RADRC by solving particle swarm optimization–differential evolution (PSO-DE) hybrid intelligent optimization algorithm under strong nonlinear inequality constraints for the separately decoupled SISO systems. Then, the model error, uncertainty time delay, internal and external disturbances are considered as total disturbance. Comprehensive simulation results are shown by comparison of the effective open-loop transfer function (EOTF) method and proportional-integral-derivative (PID) control method, which are widely used for decoupling. The practical validation of the refrigeration system control shows well that the proposed decoupled optimal control method is more effective and practical.</p>