Abstract Trigeminal sensorimotor activity stimulates arousal and cognitive performance, likely through activation of the locus coeruleus (LC). In this study we investigated, in normal subjects, the effects of bilateral trigeminal nerve stimulation (TNS) on the LC-dependent P300 wave, elicited by an acoustic oddball paradigm. Pupil size, a proxy of LC activity, and electroencephalographic power changes were also investigated. Before TNS/sham-TNS, pupil size did not correlate with P300 amplitude across subjects. After TNS but not sham-TNS, a positive correlation emerged between P300 amplitude and pupil size within frontal and median cortical regions. TNS also reduced P300 amplitude in several cortical areas. In both groups, before and after TNS/sham-TNS, subjects correctly indicated all the target stimuli. We propose that TNS activates LC, increasing the cortical norepinephrine release and the dependence of the P300 upon basal LC activity. Enhancing the signal-to-noise ratio of cortical neurons, norepinephrine may improve the sensory processing, allowing the subject to reach the best discriminative performance with a lower level of neural activation (i.e., a lower P300 amplitude). The study suggests that TNS could be used for improving cognitive performance in patients affected by cognitive disorders or arousal dysfunctions.