Complex sensor arrays prohibit practical deployment of existing wearables-based algorithms for free-living analysis of muscle and joint mechanics. Machine learning techniques have been proposed as a potential solution, however, they are less interpretable and generalizable when compared to physics-based techniques. Herein, we propose a hybrid method utilizing inertial sensor- and electromyography (EMG)-driven simulation of muscle contraction to characterize knee joint and muscle mechanics during walking gait. Machine learning is used only to map a subset of measured muscle excitations to a full set thereby reducing the number of required sensors. We demonstrate the utility of the approach for estimating net knee flexion moment (KFM) as well as individual muscle moment and work during the stance phase of gait across nine unimpaired subjects. Across all subjects, KFM was estimated with 0.91%BW•H RMSE and strong correlations (r = 0.87) compared to ground truth inverse dynamics analysis. Estimates of individual muscle moments were strongly correlated (r = 0.81-0.99) with a reference EMG-driven technique using optical motion capture and a full set of electrodes as were estimates of muscle work (r = 0.88-0.99). Implementation of the proposed technique in the current work included instrumenting only three muscles with surface electrodes (lateral and medial gastrocnemius and vastus medialis) and both the thigh and shank segments with inertial sensors. These sensor locations permit instrumentation of a knee brace/sleeve facilitating a practically deployable mechanism for monitoring muscle and joint mechanics with performance comparable to the current state-of-the-art.