This study proposes a system design scheme of fault detection, isolation, and accommodation algorithms for the actuator fault of a fixed-wing unmanned aerial vehicle (FW-UAV) by considering system nonlinearity, external disturbance, and multi-actuator faults. The fault diagnosis scheme consists of a comprehensive observer and a bank of fault isolation estimators designed based on the actuator of the FW-UAV. In the diagnosis module, the system model is transformed into two systems by introducing a transformation matrix, so that both the actuator faults and the system disturbance are separated. Then, the concept of equivalent output injection is applied to construct a comprehensive observer to detect the actuator fault and estimate the unknown system disturbance. In the isolation estimation module, a set of sliding mode observers (SMOs) is constructed to isolate the multi-actuator faults, which reveals the fault source precisely. The stability analysis of the proposed SMOs was derived from the solution of linear matrix inequalities. In the event of a fault, the fault estimation provided by the fault diagnosis solution is used to accommodate the fault effects, while maintaining good attitude control and position tracking performance of the FW-UAV. The effectiveness of the proposed scheme is verified by the simulation model of de Havilland DHC-2 ‘Beaver’ aircraft in different fault cases.