Diabetic encephalopathy, a severe complication of diabetes mellitus, is characterized by neuroinflammation and aberrant synaptogenesis in the hippocampus leading to cognitive decline. Mammalian target of rapamycin (mTOR) is associated with cognition impairment. Nuclear factor-κB (NF-κB) is a transcription factor of proinflammatory cytokines. Although mTOR has been ever implicated in processes occurring in neuroinflammation, the role of this enzyme on NF-κB signaling pathway remains unclear in diabetic encephalopathy. In the present study, we investigated whether mTOR regulates the NF-κB signaling pathway to modulate inflammatory cytokines and synaptic plasticity in hippocampal neurons. In vitro model was constructed in mouse HT-22 hippocampal neuronal cells exposed to high glucose. With the inhibition of mTOR or NF-κB by either chemical inhibitor or short-hairpin RNA (shRNA)-expressing lentivirus-vector, we examined the effects of mTOR/NF-κB signaling on proinflammatory cytokines and synaptic proteins. The diabetic mouse model induced by a high-fat diet combined with streptozotocin injection was administrated with rapamycin (mTOR inhibitor) and PDTC (NF-κB inhibitor), respectively. High glucose significantly increased mTOR phosphorylation in HT-22 cells. While inhibiting mTOR by rapamycin or shmTOR significantly suppressed high glucose-induced activation of NF-κB and its regulators IKKβ and IκBα, suggesting mTOR is the upstream regulator of NF-κB. Furthermore, inhibiting NF-κB by PDTC and shNF-κB decreased proinflammatory cytokines expression (IL-6, IL-1β, and TNF-α) and increased brain-derived neurotrophic factor (BDNF) and synaptic proteins (synaptophysin and PSD-95) in HT-22 cells under high glucose conditions. Besides, the mTOR and NF-κB inhibitors improved cognitive decline in diabetic mice. The inhibition of mTOR and NF-κB suppressed mTOR/NF-κB signaling pathway, increased synaptic proteins, and improved ultrastructural synaptic plasticity in the hippocampus of diabetic mice. Activating mTOR/NF-κB signaling pathway regulates the pathogenesis of diabetic encephalopathy, such as neuroinflammation, synaptic proteins loss, and synaptic ultrastructure impairment. The findings provide the implication that mTOR/NF-κB is potential new drug targets to treat diabetic encephalopathy.