A real-time operating optimized method of multi-input and multi-output continuous manufacture procedure includes steps as follows: first, using plurality of pivotal operation conditions in the manufacture procedure as optimized variables, and using the technical target associating with the pivotal operation conditions as the objective function, then, calculating on line the grades vector between pivotal operation conditions and the technical target at current time according to historical data of pivotal operation conditions and the technical target, using correlation integral method or other methods, at last, using this grades vector to define the adjustment direction of the operation conditions. When the grades vector is positive or negative, the pivotal operation conditions should be adjusted in order to change the grades vector to zero.