While newer designs and control approaches are being proposed for rehabilitation robots, vital information from the human musculoskeletal system should also be considered. Incorporating knowledge about joint biomechanics during the development of robot controllers can enhance the safety and performance of robot-aided treatments. In this article, the optimal path or trajectories of a parallel ankle rehabilitation robot were generated by minimizing joint reaction moments and the tension along ligaments and muscle-tendon units. The simulations showed that using optimized robot paths, user efforts could be reduced to 80%, thereby ensuring less strain on weaker or stiffer ligaments, etc. Additionally, to limit the moments applied by the robot in stiff or constrained directions, the intended robot path was modified to move the commanded position in the direction opposite to that of the position error. Such online modification of the robot path can lead to a reduction in forces applied by a robot to the subject. Simulation results and experimental findings with healthy subjects using an ankle rehabilitation robot prototype and subsequent statistical analysis further validated that path modification based on ankle joint biomechanics results in a reduction in undesired forces experienced by human users during treatment.