In this article, we present an integrated human-in-the-loop simulation paradigm for the design and evaluation of a lower extremity exoskeleton that is elastically strapped onto human lower limbs. The exoskeleton has three rotational DOFs on each side and weighs 23 kg. Two torque compensation controllers of the exoskeleton are introduced, aiming to minimize interference and maximize assistance, respectively. Their effects on the wearer's biomechanical loadings are studied with a running motion and predicted ground reaction forces (GRFs). It is found that the added weight of the passive exoskeleton substantially increases the wearer's musculoskeletal loadings. The maximizing assistance controller reduces the knee joint torque by 31% when compared with the normal running (without exoskeleton) and by 50% when compared with the passive exoskeleton case. When compared with the normal running, this controller also reduces the hip flexion and extension torques by 31% and 38%, respectively. As a result, the peak activations of the biceps short head, gluteus maximus, and rectus femoris muscles are reduced by more than a half. Nonetheless, the axial knee joint reaction force increases for all exoskeleton cases due to the added weight and higher ground reaction forces. In summary, the results provide sound evidence of the efficacy of the proposed controllers on reducing the wearer's musculoskeletal loadings. And it is shown that the human-in-the-loop simulation paradigm presented here can be used for virtual design and evaluation of powered exoskeletons and pave the way for building optimized exoskeleton prototypes for experimental evaluation.