The article covers structural design and disturbance rejection control of a flexure-based compliant piezoelectric nanopositioning stage. The stage is devised using four-bar amplification mechanisms, auxiliary guiding mechanisms, and a compound parallelogram mechanism. Static and dynamic models of compliant mechanisms are analyzed based on a compliance matrix method. A modified Prandtl-Ishlinskii (PI) model with dead zone operators is used to describe the asymmetric hysteresis. Then, a global electromechanical dynamic model is built and identified. A comprehensive disturbance rejection controller (CDRC) combining a robust H∞ control and a disturbance observer-based (DOB) control is proposed for high trajectory tracking accuracy and anti-disturbance performance. The trajectory tracking accuracy of the stage can be up to 3 nm in experiments. As amplitudes of reference signals increases, relative tracking errors gradually decrease. System instability and oscillation caused by strong external disturbances are also reduced. Experimental results prove the effectiveness of the developed CDRC.