The large number of patients with ankle injuries and the high incidence make ankle rehabilitation an urgent health problem. However, there is a certain degree of difference between the motion of most ankle rehabilitation robots and the actual axis of the human ankle. To achieve more precise ankle joint rehabilitation training, this paper proposes a novel 3-PUU/R parallel ankle rehabilitation mechanism that integrates with the human ankle joint axis. Moreover, it provides comprehensive ankle joint motion necessary for effective rehabilitation. The mechanism has four degrees of freedom (DOFs), enabling plantarflexion/dorsiflexion, eversion/inversion, internal rotation/external rotation, and dorsal extension of the ankle joint. First, based on the DOFs of the human ankle joint and the variation pattern of the joint axes, a 3-PUU/R parallel ankle joint rehabilitation mechanism is designed. Based on the screw theory, the inverse kinematics inverse, complete Jacobian matrix, singular characteristics, and workspace analysis of the mechanism are conducted. Subsequently, the motion performance of the mechanism is analyzed based on the motion/force transmission indices and the constraint indices. Then, the performance of the mechanism is optimized according to human physiological characteristics, with the motion/force transmission ratio and workspace range as optimization objectives. Finally, a physical prototype of the proposed robot was developed, and experimental tests were performed to evaluate the above performance of the proposed robot. This study provides a good prospect for improving the comfort and safety of ankle joint rehabilitation from the perspective of human-machine axis matching.