Multi-degree of freedom piezoelectric actuators are strongly needed for industrial applications, especially when manipulating a large and heavy mirror or lens in an optical system. A novel three-degree-of-freedom piezoelectric actuator, which is driven by two pairs of piezo-stack actuator with spatial compliant mechanisms designed to guide the motion and preload the piezo-stack actuators, is herein proposed. The structure and working principle of the proposed actuator are illustrated and its kinematic characteristic is analyzed. The stiffness of the spatial compliant mechanisms is modeled, and the dynamic characteristics are analyzed, Finite Element method is utilized to validate the correctness of the stiffness modeling and the free vibration analysis of the proposed actuator. A prototype actuator is fabricated and its output performances have been tested. Working space of X ranging from -7.1 to 5.6 μm, Y ranging from -6.2 to 8.2 μm and Z ranging from -2.3 to 2.1 μm, displacement resolutions of 15/16/21 nm along X-/Y-/Z-axis and average velocities of 52.3, 82.8 and 29.5 µm/s along X-axis, Y-axis, and Z-axis with carrying load up to 2 kg and driving frequency of 500 Hz have been achieved by the prototype actuator. The method of waveform generating for the proposed actuator has been developed with the inverse hysteresis compensation, and test results indicate that the positioning accuracy of the prototype actuator in the open loop has been improved from 0.94 to 0.23 μm for a circular trajectory tracking, from 0.48 to 0.29 μmm for an elliptical trajectory tracking, and from 0.61 to 0.32 μm for a rectangular trajectory tracking with the compensated waveform of driving voltage.