Background: Sleep deprivation reduced the time to induce anesthesia by propofol and isoflurane and prolonged the time to recovery. However, it is unknown whether sleep deprivation affects the potency of inhaled anesthetics. In this study, the effect of sleep deprivation on sevoflurane anesthetic potency was explored. Methods: Ten animals received the following behavioral interventions in turn (ad libitum activity, 24 h sleep deprivation, 48 h sleep deprivation, 72 h sleep deprivation). After each behavioral intervention, the 50% effective dose for loss of righting reflex (LORR ED{}_{50}) was determined to evaluate the potency of sevoflurane in inducing unconsciousness in mice. Repeated-measures analysis of variance was used to compare our behavioral interventions statistically, post hoc multiple comparisons were made using the Bonferroni test. Results: Sleep deprivation decreased the sevoflurane LORR ED{}_{50} significantly (p = 0.0003). However, the effect of duration of sleep deprivation on LORR ED{}_{50} was not statistically significant (p > 0.9999). Conclusions: Sleep deprivation can increase the anesthetic potency of sevoflurane regardless of duration of sleep deprivation.