Wearable robots, sometimes known as exoskeletons, are incredible devices for improving human strength, reducing fatigue, and restoring impaired mobility. The control of powered exoskeletons, on the other hand, is still a challenge. This necessitates the development of a technique to simulate exoskeleton–wearer interaction. This study uses a two-dimensional human skeletal model with a powered knee exoskeleton to predict the optimal lifting motion and assistive torque. For lifting motion prediction, an inverse dynamics optimization formulation is utilized. In addition, the electromechanical dynamics of the exoskeleton DC motor are modeled in the lifting optimization formulation. The design variables are human joint angle profiles and exoskeleton motor current profiles. The human joint torque square is minimized subject to physical and lifting task constraints. Then, the lifting optimization problem is solved by the gradient-based sparse nonlinear optimizer (SNOPT). Furthermore, the optimal exoskeleton torque is implemented through a two-phase control strategy to provide optimal assistance in lifting. Experimental validations of the optimal control with 6 Nm and 16 Nm maximum assistive torque are presented. Both 6 Nm and 16 Nm maximum optimal assistance of the exoskeletons reduce the mean values of vastus lateralis, biceps femoris, and latissimus dorsi muscle activations compared to the lifting without the exoskeleton. However, the mean value of the vastus medialis activation is increased by a small amount for the exoskeleton case, although its peak value is reduced. Finally, the experimental results demonstrate that the proposed lifting optimization formulation and control strategy are promising for powered knee exoskeleton for lifting tasks.