In vivo load and motion in the ankle joint play a key role in the understanding of the failure mechanism and function outcomes of total ankle arthroplasty. However, a thorough understanding of the biomechanics of the ankle joint in daily activities is lacking. The objective of this study was to develop a novel lower extremity musculoskeletal multibody dynamics model with total ankle arthroplasty considering the 6 degrees of freedom of the ankle joint motions and the deformable contact mechanics of the implant, based on force-dependent kinematics method. A patient who underwent total ankle arthroplasty surgery was considered. The walking gait data of the patient was measured in a gait laboratory and used as the input for the patient-specific musculoskeletal modeling. The predictions from the musculoskeletal model of total ankle arthroplasty included dorsiflexion–plantar flexion, inversion–eversion, internal–external rotation, anterior–posterior translation, inferior–superior translation, and medial–lateral translation of the tibiotalar joint, the ankle contact forces, the muscle activations, and the ligament forces. The magnitudes and tendencies of the predicted results were all within reasonable ranges, as compared with the data available in the literature. The predicted peak total ankle contact force was 6.55 body weight. In addition, the peak contact forces of the lateral and medial compartments were 4.22 body weight and 2.59 body weight, respectively. This study provides a potential new platform for the design of a better ankle prosthesis, the improvement of the operation techniques of the clinicians, and the accelerated postoperative recovery of the patients.