This work examined if currently available electromyography (EMG) driven models, that are calibrated to satisfy joint moments about one single degree of freedom (DOF), could provide the same musculotendon unit (MTU) force solution, when driven by the same input data, but calibrated about a different DOF. We then developed a novel and comprehensive EMG-driven model of the human lower extremity that used EMG signals from 16 muscle groups to drive 34 MTUs and satisfy the resulting joint moments simultaneously produced about four DOFs during different motor tasks. This also led to the development of a calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the 34 MTUs. Results showed that currently available single-DOF models did not provide the same unique MTU force solution for the same input data. On the other hand, the MTU force solution predicted by our proposed multi-DOF model satisfied joint moments about multiple DOFs without loss of accuracy compared to single-DOF models corresponding to each of the four DOFs. The predicted MTU force solution was (1) a function of experimentally measured EMGs, (2) the result of physiological MTU excitation, (3) reflected different MTU contraction strategies associated to different motor tasks, (4) coordinated a greater number of MTUs with respect to currently available single-DOF models, and (5) was not specific to an individual DOF dynamics. Therefore, our proposed methodology has the potential of producing a more dynamically consistent and generalizable MTU force solution than was possible using single-DOF EMG-driven models. This will help better address the important scientific questions previously approached using single-DOF EMG-driven modeling. Furthermore, it might have applications in the development of human-machine interfaces for assistive devices.