This paper presents a fixed-time fault-tolerant adaptive neural network control scheme for the Twin-Rotor Multi-Input Multi-Output System (TRMS), which is challenging due to its complex, unstable dynamics and helicopter-like behavior with two degrees of freedom (DOFs). The control objective is to stabilize the TRMS in trajectory tracking in the presence of unknown nonlinear dynamics, external disturbances, and sensor faults. The proposed approach employs the backstepping technique combined with adaptive neural network estimators to achieve fixed-time convergence. The unknown nonlinear functions and disturbances of the system are processed via an adaptive radial basis function neural network (RBFNN), while the sensor faults are actively estimated using robust terms. The developed controller is applied to the TRMS using a decentralized structure where each DOF is controlled independently to simplify the control scheme. Moreover, the parameters of the proposed controller are optimized by the gray-wolf optimization algorithm to ensure high flight performance. The system’s stability analysis is proven using a Lyapunov approach, and simulation results demonstrate the effectiveness of the proposed controller.