In neurorehabilitation, motor performances may improve if patients could accomplish the training by overcoming mechanical loads. When the load inertia is increased, it has been found to trigger linear responses in motor-related cortices. The cortical responses, however, are unclear whether they also correlate to changes in muscular patterns. Therefore, it remains difficult to justify the magnitude of load during rehabilitation because of the gap between cortical and muscular activation. Here, we test the hypothesis that increases in load inertia may alter the muscle synergies, and the change in synergy may correlate with cortical activation. Twelve healthy subjects participated in the study. Each subject lifted dumbbells (either 0, 3, or 15 pounds) from the resting position to the armpit repetitively at 1 Hz. Surface electromyographic signals were collected from 8 muscles around the shoulder and the elbow, and hemodynamic signals were collected using functional near-infrared spectroscopy from motor-related regions Brodmann Area 4 (BA4) and BA6. Results showed that, given higher inertia, the synergy vectors differed farther from the baseline. Moreover, synergy similarity on the vector decreased linearly with cortical responses in BA4 and BA6, which associated with increases in inertia. Despite studies in literature that movements with similar kinematics tend not to differ in synergy vectors, we show a different possibility that the synergy vectors may deviate from a baseline. At least 2 consequences of adding inertia have been identified: to decrease synergy similarity and to increase motor cortical activity. The dual effects potentially provide a new benchmark for therapeutic goal setting.