Many patients with sporadic Alzheimer's disease (AD) suffer from memory impairment, anxiety- and depression. The systemic utility of N-Methyl-d-Aspartate (NMDA) receptor antagonists has been shown to be potential therapeutic target for memory loss in AD. However, there is no evidence that shows whether NMDA receptor antagonists have the same effects when these blockers are directly used within the brain regions including hippocampus. It might be an urgent to further explore the therapeutic role of NMDA receptor antagonists in behavioral abnormalities such as anxiety and depression in AD. The aim of this study was to determine whether blockade of the hippocampal NMDA receptors could attenuate neurobehavioral abnormalities in rats with sporadic AD. Twelve days after AD induction by streptozotocin (STZ), animals received either vehicle or MK-801 (NMDA receptor antagonist) in the hippocampus for 10 days. Two or five days after the last MK-801 treatment, spatial memory, anxiety- and depression-related behaviors, and inflammatory cytokines (interleukin-(IL)-6, IL-1β and tumor necrosis factor (TNF)-α) were evaluated. Our findings indicated that STZ treatment significantly elevated hippocampal inflammation, impaired spatial memory, and increased anxiety- and depression-related symptoms in rats. Interestingly, the hippocampal NMDA receptor blockade improved these neurobehavioral phenotypes and decreased inflammatory cytokines in the hippocampus of STZ-treated rats. Hippocampal NMDA receptors might be involved in neurobehavioral abnormalities via inflammation in sporadic AD.