Background: Intensive, task-oriented motor training has been associated with neuroplastic reorganization and improved upper extremity movement function after stroke. However, to optimize such training for people with moderate-to-severe movement impairment, pharmacological modulation of neuroplasticity may be needed as an adjuvant intervention.Objective: Evaluate safety, as well as improvement in movement function, associated with motor training paired with a drug to upregulate neuroplasticity after stroke.Methods: In this double-blind, randomized, placebo-controlled study, 12 subjects with chronic stroke received either atomoxetine or placebo paired with motor training. Safety was assessed using vital signs. Upper extremity movement function was assessed using Fugl-Meyer Assessment, Wolf Motor Function Test, and Action Research Arm Test at baseline, post-intervention, and 1-month follow-up.Results: No significant between-groups differences were found in mean heart rate (95% CI, –12.4–22.6; p = 0.23), mean systolic blood pressure (95% CI, –1.7–29.6; p = 0.21), or mean diastolic blood pressure (95% CI, –10.4–13.3; p = 0.08). A statistically significant between-groups difference on Fugl-Meyer at post-intervention favored the atomoxetine group (95% CI, 1.6–12.7; p = 0.016).Conclusion: Atomoxetine combined with motor training appears safe and may optimize motor training outcomes after stroke.