In this paper, a novel robust back-stepping fault- tolerant control scheme is proposed, which enables hypersonic reentry vehicles with model uncertainties to accurately track the attitude commands under the condition of both unknown actuator faults and external disturbances. Firstly, a control-oriented hypersonic reentry vehicle model is established on the basis of regarding three factors mentioned above as lumped disturbance. Then, a fixed-time observer is used to achieve the fixed-time lumped disturbance estimation. Based on the disturbance observer and back-stepping technology, the proposed fault-tolerant control laws are designed to ensure control performance. Meanwhile, the “differential explosion” problem is solved by the sigmoid function-based tracking differentiator. Finally, the stability and effectiveness of the proposed controller are verified from theoretical analysis and extensive numerical simulations respectively.