Sleep disturbance affects brain health, with research in rodents showing that both hippocampal memory and synaptic plasticity are impaired following sleep deprivation (SD). However, most studies have used males, overlooking sex as a biological variable (SABV). Given estradiol’s neuroprotective role in the female hippocampus, we hypothesized that the consequences of SD on memory and synaptic plasticity are modulated by sex and/or sex hormones. This review compares SD effects in males to 1) the limited findings in sleep-deprived females, and 2) the effects of estradiol in non-sleep deprived females. The few studies conducted in females suggest that memory deficits post-SD depend on hormonal state. Estradiol in non-sleep-deprived females also modulates hippocampal mechanisms of synaptic plasticity that are impaired by SD in males. While the currently available data is limited, it does hint towards sex-specific effects of SD, and emphasizes the importance of incorporating SABV in future research.