Cross-axis coupling effect and multiple disturbances can cause degradation of the nanomanipulation system performance and bring great challenges to controller design. Most control schemes ignore the coupling effect directly or regard it as a part of lumped disturbances, which cannot fully consider the influence of cross-axis coupling. To obtain better control performance, this paper proposes an inverse system decoupling algorithm to solve the cross-axis coupling effect. In addition, considering that the nanomanipulation system is affected by multiple disturbances, the sliding mode control is introduced to ensure the system's anti-disturbance capability in this paper. Meanwhile, considering the large chattering phenomenon caused by high switching gain in sliding mode control, a composite method based on generalized proportional integral observer (GPIO) is proposed to reduce chattering. With the disturbance estimation provided by GPIO for feedforward compensation, the sliding mode controller can take a smaller value for the switching gain without sacrificing disturbance rejection performance. Finally, the feasibility and effectiveness of the proposed method are validated by simulation.