We have developed a neuromodulation approach that targets peripheral nerves and utilizes their afferents as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) approach on physiological responses to acute stress induction. TEN was targeted to the ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents (C2/C3) using high-frequency, pulse-modulated electrical currents. Compared to active sham stimulation, TEN significantly suppressed sympathetic activity in response to acute stress without impeding cognitive performance. This sympatholytic action of TEN was indicated by significant suppression of heart rate variability changes, galvanic skin responses, and salivary α-amylase levels in response to stress. These observations are consistent with the hypothesis that TEN acted partially by modulating activity in the locus coeruleus and subsequent noradrenergic signaling. Dampening sympathetic tone using TEN in such a manner represents a promising approach to managing daily stress and improving brain health.