Cranial electrotherapy stimulation (CES) has a long history in the clinical sciences as a complementary therapy for treating disorders such as insomnia, depression, and anxiety. Research suggests that CES may also prove valuable for altering physiology and behavior in healthy, non-clinical samples, though data are equivocal and show a high risk of bias. The present study used a double-blind, placebo-controlled, crossover design to examine the effects of CES on emotional, physiological, biochemical, and behavioral responses to acute stress. Healthy male participants visited the laboratory for two sessions, one involving active CES administration (20 min at 100 µA and 0.5 Hz) and one involving sham, inactive CES. During each session, participants were placed under stress (threat of torso shock) while performing challenging cognitive tests, and we measured emotional, biochemical (alpha amylase, cortisol), physiological (heart rate, respiration rate, heart rate variability, pupil diameter), and cognitive behavioral (memory, decision-making, spatial orienting) responses. Outcome metrics were compared using repeated measures analysis of variance (ANOVA) and planned comparisons. The stress induction reliably modulated measures of sympathetic adrenal medullary (SAM) activity but not hypothalamic–pituitary–adrenal (HPA) axis activity. Active versus placebo CES did not significantly influence any emotional, biochemical, or physiological outcome measure. Active CES did, however, selectively increase performance on a recognition memory test and degrade performance on a perceptual decision-making test. Overall, we find no compelling evidence that CES reliably modulates the nervous system’s immediate response to acute stress, suggesting its limited utility for sustaining performance in high-stakes domains involving stress exposure.