Fine motor control is achieved through the coordinated activation of groups of muscles, or “muscle synergies.” Muscle synergies change after stroke as a consequence of the motor deficit. We investigated the pattern and longitudinal changes in upper limb muscle synergies during therapy in a largely unconstrained movement in patients with a broad spectrum of poststroke residual voluntary motor capacity. Electromyography (EMG) was recorded using wireless telemetry from 6 muscles acting on the more-affected upper body in 24 stroke patients at early and late therapy during formal Wii-based Movement Therapy (WMT) sessions, and in a subset of 13 patients at 6-month follow-up. Patients were classified with low, moderate, or high motor-function. The Wii-baseball swing was analyzed using a non-negative matrix factorization (NMF) algorithm to extract muscle synergies from EMG recordings based on the temporal activation of each synergy and the contribution of each muscle to a synergy. Motor-function was clinically assessed immediately pre- and post-therapy and at 6-month follow-up using the Wolf Motor Function Test, upper limb motor Fugl-Meyer Assessment, and Motor Activity Log Quality of Movement scale. Clinical assessments and game performance demonstrated improved motor-function for all patients at post-therapy (p < 0.01), and these improvements were sustained at 6-month follow-up (p > 0.05). NMF analysis revealed fewer muscle synergies (mean ± SE) for patients with low motor-function (3.38 ± 0.2) than those with high motor-function (4.00 ± 0.3) at early therapy (p = 0.036) with an association trend between the number of synergies and the level of motor-function. By late therapy, there was no significant change between groups, although there was a pattern of increase for those with low motor-function over time. The variability accounted for demonstrated differences with motor-function level (p < 0.05) but not time. Cluster analysis of the pooled synergies highlighted the therapy-induced change in muscle activation. Muscle synergies could be identified for all patients during therapy activities. These results show less complexity and more co-activation in the muscle activation for patients with low motor-function as a higher number of muscle synergies reflects greater movement complexity and task-related phasic muscle activation. The increased number of synergies and changes within synergies by late-therapy suggests improved motor control and movement quality with more distinct phases of movement.