Molecular hydrogen (H2) has been suggested as an agent capable of exerting neuromodulating effects; yet, its potential to affect brain circuits linked to alertness remains poorly examined. In this randomized controlled cross-over pilot trial, we compared acute effects of single-dose hydrogen-rich water (HRW) and caffeine on estimates by the Visual Analog Scale (VAS) for alertness and on Attention Network Test (ANT) subscales in 23 young healthy men and women (21.6 ± 1.3 years) who were sleep-deprived for 24 hours. Caffeine induced a significant increase in VAS-estimated alertness (1.6 points, P = 0.01); HRW also increased VAS alertness for 1.7 points on average (P = 0.003). Both caffeine and HRW acutely affected markers of alertness in young sleep-deprived men and women. Caffeine induced a significant drop in alerting (19.9%, P = 0.01) and executive control in a 15-min follow up (7.3%, P = 0.03), while HRW caused a significant reduction in the orientation at post-administration (2.4%, P = 0.05). However, no differences were found between interventions (treatment vs. time interaction) for all evaluated outcomes of alertness (P > 0.05), with the effects similar among interventions. HRW displayed no side effects and, therefore, might be advanced as a safe and effective alternative to caffeine for sleep deprivation, although more studies are needed to corroborate and expand these preliminary findings.