The traditional control method cannot accurately decouple the multiinput and multioutput (MIMO) nonlinear system due to the characteristics of heavy delay, and strong coupling, which leads to lower control precision. An improved particle swarm optimization (PSO) algorithm on basis of the immune mechanism was proposed in this study, and this algorithm was used to optimize PID neural network (PIDNN) weights to form a new PIDNN controller. Two new PIDNN controllers were used to control the 2in2out coupling system to reduce the coupling effect of the system. The simulation results showed that this method exhibited better dynamic and static characteristics than traditional PID decoupling control algorithm. It could provide some references for the decoupling problem in the field of control.