Piezoelectric actuators (PEA) act an important role in active vibration control area due to the advantages of fast response, high output force, small size and light weight. A 6-axis orthogonal vibration isolation platform based on PEAs is designed, which satisfies the demands of heavy payload, small installation space and multi degree of freedom vibration isolation. The dynamic model of the six-axis orthogonal vibration isolation platform with PEAs is established using Newton-Euler method. With the layout of six PEAs around the axis of symmetry, the dynamic equations could be decoupled into two single-input-single-output (SISO) subsystems and two multi-input-multi-output (MIMO) subsystems. Based on the modal superposition method, the two MIMO subsystems are further decoupled. The control strategy for each SISO system is developed with LQR control method. To evaluate the effectiveness of the control method, the simulation and verification experiment are conducted. The simulation result and experimental data indicate that the decoupling control of the proposed six-axis orthogonal vibration isolation platform with piezoelectric actuators effectively reduces the vibration response of payload within the target frequency range of 20 Hz to 200 Hz.