The large volume and windward area of the heavy-duty semi-rigid airship (HSA) result in a large turning radius when the HSA passes through every mission point. In this study, a multi-mission-point route planning method for HSA based on the genetic algorithm and greedy strategy is proposed to direct the HSA maneuver through every mission point along the optimal route. Firstly, according to the minimum flight speed and the maximum turning slope angle of the HSA during turning, the minimum turning radius of the HSA near each mission point is determined. Secondly, the genetic algorithm is used to determine the optimal flight sequence of the HSA from the take-off point through all the mission points to the landing point. Thirdly, based on the optimal flight sequence, the shortest route between every two adjacent mission points is obtained by using the route planning method based on the greedy strategy. By determining the optimal flight sequence and the shortest route, the optimal route for the HSA to pass through all mission points can be obtained. The experimental results show that the method proposed in this study can generate the optimal route with various conditions of the mission points using simulation studies. This method reduces the total voyage distance of the optimal route by 18.60% on average and improves the flight efficiency of the HSA.