Inhibitory control processes are known to be modulated by working memory demands. However, the neurobiological mechanisms behind these modulations are inconclusive. One important system to consider in this regard is the locus coeruleus (LC) norepinephrine (NE) system. In the current study the role of the LC-NE system by means of pupil diameter recordings that are integrated with neurophysiological (EEG) and source localization data were examined. A combined mental-rotation Go/Nogo task was used. The results show that increases in working memory load complicate response inhibition processes. On a neurophysiological level these effects were reflected by specific modulations in event-related potentials (ERPs) reflecting motor inhibition processes (i.e., Nogo-P3). Attentional selection processes (reflected by the P1 and N1) as well as pre-motor inhibition or conflict monitoring processes (reflected by the Nogo-N2) were not affected. Activity of the LC-NE systems, as indexed by the pupil diameter data, predicted neurophysiological processes selectively in the Nogo-P3 time range. Source localization analyses suggest that this modulation occurs in the right middle and inferior frontal gyrus. The study provides evidence that the LC-NE system is an important neurobiological system modulating the effects of working memory load on response inhibition processes. More specifically, it modulates a subset of dissociable cognitive processes that are related to prefrontal cortical regions. Hum Brain Mapp 38:68–81, 2017.