There is provided a control system for a plant and an internal combustion engine, which is capable of enhancing controllability and control accuracy in controlling a plurality of control amounts while eliminating a mutual interaction existing between a plurality of control inputs and the control amounts. The control system 1 for the plant 90 in which a mutual interaction exists between TH_cmd and Liftin_cmd as control inputs and PB and Gcyl as control amounts calculates the two control inputs TH_cmd and Liftin_cmd as two non-interacting inputs for causing PB and Gcyl to follow target values PB_cmd and Gcyl_cmd, respectively, the two control inputs TH_cmd and Liftin_cmd eliminating the mutual interaction, with a predetermined algorithm in which a predetermined response-specifying control algorithm (equations (2) to (8)) and a predetermined non-interacting control algorithm (equation (9)) are combined based on a plant model (equation (20)) formed by modeling the plant 90 into a discrete-time system model.