Objective: Current clinical biomechanics involves lengthy data acquisition and time-consuming offline analyses and current biomechanical models cannot be used for real-time control in man-machine interfaces. We developed a method that enables online analysis of neuromusculoskeletal function in vivo in the intact human. Methods: We used electromyography (EMG)-driven musculoskeletal modeling to simulate all transformations from muscle excitation onset (EMGs) to mechanical moment production around multiple lower-limb degrees of freedom (DOFs). We developed a calibration algorithm that enables adjusting musculoskeletal model parameters specifically to an individual’s anthropometry and force-generating capacity. We incorporated the modeling paradigm into a computationally efficient, generic framework that can be interfaced in real-time with any movement data collection system. Results: The framework demonstrated the ability of computing forces in 13 lower-limb muscle-tendon units and resulting moments about three joint DOFs simultaneously in real-time. Remarkably, it was capable of extrapolating beyond calibration conditions, i.e. predicting accurate joint moments during six unseen tasks and one unseen DOF. Conclusion: The proposed framework can dramatically reduce evaluation latency in current clinical biomechanics and open up new avenues for establishing prompt and personalized treatments, as well as for establishing natural interfaces between patients and rehabilitation systems. Significance: The integration of EMG with numerical modeling will enable simulating realistic neuromuscular strategies in conditions including muscular/orthopedic deficit, which could not be robustly simulated via pure modeling formulations. This will enable translation to clinical settings and development of healthcare technologies including real-time bio-feedback of internal mechanical forces and direct patient-machine interfacing.