Despite the large amount of successful existing methods and frameworks for planning sets of multiple Unmanned Aerial Systems (UAS), there are still lack of coordination frameworks capable of coping with real-world operational conditions. This paper presents U-Plan, an integrated management framework for the coordination of multi-UAS missions. U-Plan is designed to plan, schedule, monitor, and replan a heterogeneous set of UAS to complete Points of Interest (PoIs) visiting missions while ensuring that all generated trajectories are safe, feasible, and compliant with the required PoIs’ arrival times, UAS kinematics and energetic constraints, and the existing 3D No-FLy Zones (NFZs). U-Plan is designed as a practical tool for strongly dynamic missions, and is built upon three core components: 1) an NFZ-aware route computation method that explicitly accounts for NFZs prior to the Vehicle Routing Problem (VRP) optimization, resulting in shorter NFZ-safe routes; 2) a trajectory planning module that ensures the generation of kinematically-feasible trajectories for fixed-wing UAS; and 3) a mission supervision module for real-time monitoring and replanning in case of changes in UAS, mission, wind speed, or airspace restrictions. It was implemented and validated by interfacing with professional-grade Visionair Ground Control Station Software and the VECTOR-SIL Software-in-the-Loop simulator, which realistically replicates the behavior of certified fixed-wing autopilots under various weather conditions. The validation shows U-Plan’s capacity to efficiently satisfy complex mission requirements with strong scalability. Due to its high computational efficiency, U-Plan enables online mission replanning, allowing UAS fleets to seamlessly adapt to changes typical of real-world operational scenarios.