The contribution of selective serotonin reuptake inhibitors (SSRIs) to motor learning by inducing motor cortical plasticity remains controversial given diverse findings from positive preclinical data to negative findings in recent clinical trials. To empirically address this translational disparity, we use functional magnetic resonance imaging (fMRI) in a double-blind, randomized controlled study powered to assess whether 20 mg escitalopram improves sequence-specific motor performance and modulates cortical motor response in 64 healthy female participants. We found decreased left premotor cortex responses during sequence-specific learning performance comparing single dose and steady escitalopram state. Escitalopram plasma-levels negatively correlated with the premotor cortex response. We did not find evidence in support of improved motor performance after a week of escitalopram-intake. These findings do not support the conclusion that 1-week escitalopram intake increases motor performance but could reflect early adaptive plasticity with improved neural processing underlying similar task performance when steady peripheral escitalopram levels are reached.