Rationale <p>Cognitive control is crucial for optimal daily functioning and for emotional well-being. Cognitive control has been shown to be modified by experimental manipulations under widely differing experimental conditions, including cognitive training, and pharmacological intervention mainly probing catecholaminergic systems with little focus on the serotonergic system.</p> Objectives <p>To explore the role of serotonin on cognitive control in emotional and non-emotional settings.</p> Methods <p>Behavioral, electrodermal and prefrontal activity measures were evaluated to compare the effects of single-session task repetition and single-dose serotonergic intervention with escitalopram on cognitive control in healthy participants, using cognitive and emotional Stroop tasks.</p> Results <p>For cognitive Stroop, task repetition improved performance both ‘on-line’ within an ongoing task and ‘off-line’ after a four-hour delay, and escitalopram had no additional effects on this. In emotional Stroop, escitalopram enhanced the practice-related performance gain, starting from the second stimulus of each block. Compared to placebo, escitalopram also significantly reduced overall rate of premature responses. Regarding brain activation, escitalopram significantly reduced prefrontal activity during cognitive and even more so during emotional Stroop task. Lastly, electrodermal response showed significant habituation during cognitive but not emotional Stroop, in an effect that was not significantly modified by escitalopram.</p> Conclusions <p>Cognitive control in emotional and non-emotional settings may respond differently to behavioral and pharmacological manipulations. Escitalopram may selectively improve cognitive control in an emotional setting compared to cognitive control in non-emotional settings.</p>