In this article, a novel approach based on game theory is presented for multi-objective optimal synthesis of four-bar mechanisms. The multi-objective optimization problem is modelled as a Stackelberg game. The more important objective function, tracking error, is considered as the leader, and the other objective function, deviation of the transmission angle from 90° (TA), is considered as the follower. In a new approach, a group method of data handling (GMDH)-type neural network is also utilized to construct an approximate model for the rational reaction set (RRS) of the follower. Using the proposed game-theoretic approach, the multi-objective optimal synthesis of a four-bar mechanism is then cast into a single-objective optimal synthesis using the leader variables and the obtained RRS of the follower. The superiority of using the synergy game-theoretic method of Stackelberg with a GMDH-type neural network is demonstrated for two case studies on the synthesis of four-bar mechanisms.