Perilla frutescens (PF) is a traditional medicine herb in East Asian countries. In present study, we evaluated the effects of fermented PF (FPF) in sleep deprivation induced cognitive impairment model. The mice were pretreated with FPF for 3 days via oral administration before sleep deprivation (SD) for 72 h. SD impaired cognitive function and these results were restored by FPF administration in mice. Also, SD exposure significantly increased cellular oxidative damage and neuronal cell death in hippocampus. FPF may prevented this impairment in hippocampus. Furthermore, the FPF inhibited glutamate-induced both cell death and ROS accumulation in hippocampal neuron cells in vitro. Also, we confirmed FPF has radical scavenging activities in both DPPH and ABTS assay. These founding indicated that FPF has antioxidant and neuroprotective effects through radical scavenging activities. Additionally, SD exposure decreased the level of brain-derived nerve growth factor (BDNF) and regained by FPF treatment. We evaluated to these changes whether associated with cognitive improvement effect of FPF at behavior test. The treatment of TrkB antagonist was significantly abolished cognitive abilities and hippocampal neuronal cell survival in FPF-treated mice. These results suggest that FPF has a therapeutic potential for cognitive improvement by regulating oxidative stress and activation of BDNF/TrkB signaling pathway. Therefore, FPF could be used as a novel herbal medicine for the treatment of cognitive and memory function.