The autonomous obstacle avoidance of UAV (unmanned aerial vehicle) is the basis of completing complex tasks, and the obstacle avoidance performance directly affects the efficiency of UAV performing tasks. Aiming at the obstacle avoidance problem of UAV with external disturbance, a design method of anti-disturbance and obstacle avoidance guidance law based on model prediction was proposed. The disturbance observer was designed to estimate the external disturbance in the system dynamics, and the auxiliary guidance law was designed based on Lyapunov function method to establish the stability constraints. Combining the first two with MPC (model predictive control), the relationship between UAV and obstacles was considered in the MPC optimization solution, and the horizontal linear velocity and yaw angular velocity commands were solved according to the designed guidance law to realize the obstacle avoidance of UAV. The numerical simulation and physical flight verification of the proposed obstacle avoidance guidance law show the effectiveness of the proposed method.