Sleep deprivation represents a significant public health problem in countries around the world, resulting in significant impairments in memory and performance. The hippocampus is particularly susceptible to the effects of sleep deprivation. Increasingly, studies suggest sex-specific behavioral differences occur following acute sleep deprivation, but almost all molecular studies have examined changes in males. Consequently, we investigated changes in gene expression following acute sleep deprivation in female mice at different estrous stages. Following one week of individual housing and pre-handling for three days, mice were sleep deprived using gentle handling (tapping and cage shakes as needed) for five hours and brain regions dissected. Non-sleep deprived mice were sacrificed at the same time to avoid any circadian confounds in gene expression. Estrous stage of the mouse was determined post-sacrifice. Using RNA-seq, we found that females appeared more resilient to changes in gene expression in the hippocampus after acute sleep deprivation compared to male mice. Compared to the more than 650 significant changes in hippocampal gene expression seen in males, we found only 99 genes in the hippocampus were differentially expressed in females following acute sleep deprivation. In proestrus, female mice had no significant differential gene expression in the hippocampus after sleep deprivation. Although it is remains to be determined what the impact of this molecular resilience in gene expression means behaviorally, these results clearly demonstrate that sleep deprivation induces sex-specific differences and that hormonal changes in female mice provide some resilience to acute sleep deprivation.