A guidance approach with obstacle avoidance is proposed for maneuvering target interception. Firstly, by decomposing the constrained optimal guidance problem into two associated subproblems, the overall scheme of guidance is presented. Secondly, to improve the guidance accuracy against the maneuvering target, an MPC controller with disturbance estimation is designed, which transforms the global optimization problem into a finite-horizon optimal control problem. An auxiliary controller is also developed to ensure the system’s stability. Then, to achieve obstacle avoidance without affecting the guidance accuracy, a unified function is built to assess the threats from obstacles of different shapes, based on which the optimal guidance-obstacle avoidance model is established. Finally, to solve the above optimization problems, a hybrid solver is developed based on the adaptive moment estimation (Adam) algorithm, whose output will serve as the real-time guidance command. The numerical simulation results show that the guidance approach presented in this paper can achieve precise guidance and obstacle avoidance in various scenarios, and the Monte Carlo experiment further demonstrates the robustness and computation efficiency of the approach.