The purpose of this computational study was to analyze the effects of different mobile-bearing (MB) total knee replacement (TKR) designs on knee joint biomechanics. A validated musculoskeletal model of the lower right extremity implanted with a cruciate-retaining fixed-bearing TKR undergoing a squat motion was adapted for three different MB TKR design variants: (I) a commercially available TKR design allowing for tibial insert rotation about the tibial tray with end stops to limit the range of rotation, (II) the same design without end stops, and (III) a multidirectional design with an additional translational degree-of-freedom (DoF) and end stops. When modeling the MB interface, two modeling strategies of different joint topologies were deployed: (1) a six DoF joint as a baseline and (2) a combined revolute-prismatic joint (two DoF joint) with end stops in both DoF. Altered knee joint kinematics for the three MB design variants were observed. The commercially available TKR design variant I yielded a deviation in internal-external rotation of the tibial insert relative to the tray up to 5° during knee flexion. Compared to the multidirectional design variant III, the other two variants revealed less femoral anterior-posterior translation by as much as 5 mm. Concerning the modeling strategies, the two DoF joint showed less computation time by 68%, 80%, and 82% for design variants I, II, and III, respectively. However, only slight differences in the knee joint kinematics of the two modeling strategies were recorded. In conclusion, knee joint biomechanics during a squat motion differed for each of the simulated MB design variants. Specific implant design elements, such as the presence of end stops, can impact the postoperative range of knee motion with regard to modeling strategy, and the two DoF joint option tested accurately replicated the results for the simulated designs with a considerably lower computation time than the six DoF joint. The proposed musculoskeletal multibody simulation framework is capable of virtually characterizing the knee joint dynamics for different TKR designs.