<p>This study investigates the attitude regulation of in-orbit spacecraft with liquid sloshing, external perturbations, inertial uncertainties, and input saturation. A second-order dynamic model is derived from the theorem of angular momentum and Newton’s laws to describe the attitude-orbit motions of spacecraft. A nonlinear pendulum model with three degrees of freedom is employed to simulate the liquid sloshing. Based on the two models, an orbit controller is employed to keep the orbit position unchanged to reduce the effects of the orbit dynamics on the attitude motion, and a control law is proposed to regulate the attitude of the in-orbit rigid-liquid coupled spacecraft with external perturbations and inertial uncertainties. The proposed attitude control law is implemented by a fully actuated system controller and a continuous saturation compensator. The fully actuated system controller is constructed based on an extended state observer and can realize attitude control with unwinding-free performance and high precision. The saturation compensator mitigates the effects of input saturation during the control execution period. Lyapunov’s direct method is applied to demonstrate the system stability of the rigid-liquid coupled spacecraft. Numerical simulations show the effectiveness of the designed attitude control law.</p>