A model-free self-tuning controller (STC) based on online support vector regression (SVR) is proposed to control nonlinear and multi-input multi-output (MIMO) systems in this paper. MIMO proportional-derivative-integral (PID) controller parameters are optimized via introduced MIMO STC architecture based on SVR. The closed-loop margin notion is enhanced for MIMO type STC architectures. The adjustment mechanism is composed of only STC structure, and system model is not needed. Optimal values of STC parameters are obtained using the tracking error without any need to estimate the controlled system dynamics. In the proposed control architecture, the prediction capability of SVR and the robustness of the PID controller are combined. The success of the introduced SVR-based MIMO STC has been assessed by simulations carried out on the nonlinear Van de Vusse benchmark system. Acquired results justify that proposed structure achieves good control performance.