The two-wheel inverted pendulum mobile robot (TWIPMR) has high nonlinearities, uncertain parameters, and input disturbance. Based on the sliding mode control (SMC) and the disturbance observer, this paper proposes an adaptive controller for the TWIPMR with three independent motions. The novel disturbance observer with the saturation of the hardware is proposed to estimate the input disturbance of the TWIPMR system and reduce the computational cost of the existing observers. The low-pass regulated filters are integrated into the design procedure to eliminate the high-order harmonic and radio frequency interference of the TWIPMR system. The stability of the closed-loop system under the effect of the AFTSMC controller is ensured systematically through Lyapunov’s second law. The simulation results demonstrate the effectiveness of the proposed controller and disturbance observer.