Underactuated ships are facing problems of interference of time-varying multi-source disturbance and sudden changes in control force at the turning points during path following. Aiming at the above two problems, this paper proposed an optimal control method by combining the extended state observer with model predictive control. Firstly, the ESO extended state observer was designed to compensate for time-varying multi-source disturbance and provide low-frequency control input. Secondly, a nonlinear MPC controller was designed to optimize the control force. Finally, the stability of the ESO-MPC cascade controller was proved based on the nonlinear separation principle. The simulation comparison with active disturbance rejection control method and MPC control method verified the effectiveness of the proposed ESO-MPC cascade control method.