General anesthesia with sevoflurane is associated with an increased incidence of postoperative cognitive dysfunction. Previous studies have shown that sevoflurane anesthesia can affect the integrity and function of basal forebrain cholinergic neurons (BFCNs) which are essential for learning and memory. However, the underlying mechanisms remain largely unknown. Here, we demonstrated that exposure to 2.5% sevoflurane induced significant loss of BFCNs and caused impairments of the spatial and the fear memory. Further, sevoflurane exposure significantly reduced the level of nerve growth factor (NGF), an important factor for the survival and phenotype maintenance of BFCNs, by disrupting its synthesis pathways in the brain. More importantly, NGF administration not only prevented the loss of BFCNs but also ameliorated the cognitive impairments in sevoflurane-treated mice. Our findings indicate that NGF metabolic dysfunction contributes to sevoflurane-associated BFCNs degeneration and subsequent cognitive deficits.