Electromyography (EMG)-based interfaces are trending toward continuous, simultaneous control with multiple degrees of freedom. Emerging methods range from data-driven approaches to biomechanical model-based methods. However, there has been no direct comparison between these two types of continuous EMG-based interfaces. The aim of this study was to compare a musculoskeletal model (MM) with two data-driven approaches, linear regression (LR) and artificial neural network (ANN), for predicting continuous wrist and hand motions for EMG-based interfaces. Six able-bodied subjects and one transradial amputee subject performed (missing) metacarpophalangeal (MCP) and wrist flexion/extension, simultaneously or independently, while four EMG signals were recorded from forearm muscles. To add variation to the EMG signals, the subjects repeated the MCP and wrist motions at various upper extremity postures. For each subject, the EMG signals collected from the neutral posture were used to build the EMG interfaces; the EMG signals collected from all postures were used to evaluate the interfaces. The performance of the interface was quantified by Pearson's correlation coefficient (r) and the normalized root mean square error (NRMSE) between measured and estimated joint angles. The results demonstrated that the MM predicted movements more accurately, with higher r values and lower NRMSE, than either LR or ANN. Similar results were observed in the transradial amputee. Additionally, the variation in r across postures, an indicator of reliability against posture changes, was significantly lower (better) for the MM than for either LR or ANN. Our findings suggest that incorporating musculoskeletal knowledge into EMG-based human-machine interfaces could improve the estimation of continuous, coordinated motion.