A moving optical axis measurement system with six degrees-of-freedom (DOF) is proposed in this study. The system is very simple and can be placed inside a flat piezoelectric micro-stage. The system comprises three two-DOF optical measurement modules, each having a quadrant photo diode (QPD), a lens, and a laser diode. These three modules and the geometric configuration of their installation allow displacement measurements with up to six-DOF to be made. A mathematical model of this system is also presented. By analyzing the sensitivity and relationship between the displacement of the stage and each of the QPD light spots, movement can be observed. Signal feedback enables multi-axis nano-scale positioning control. We also present a new six-DOF nano stage, which uses piezoelectric actuators for displacement. This stage was used to verify the proposed six-DOF measurement system. Linear and angular resolution of the system can be down to 10 nm and 0.1 arcsec. Linear and angular displacement measurement errors of this six-DOF measurement system are in the range of ±70 nm and ±0.65 arcsec.