Alzheimer’s disease is one of the most common causes of death worldwide, with poor treatment options. A tissue landmark of Alzheimer’s disease is accumulation of the anomalous protein amyloid-β in specific brain areas. Whether inflammation is an effect of amyloid-β on the Alzheimer’s disease brain, or rather it represents a cause for formation of amyloid plaques and intracellular tangles remains a subject of debate. TNFSF10, a proapoptotic cytokine of the TNF superfamily, is a mediator of amyloid-β neurotoxicity. This study demonstrates that blocking TNFSF10 by administration of a neutralizing monoclonal antibody could attenuate the amyloid- β-induced neurotoxicity in a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD). The effects of TNFSF10 neutralization on either cognitive parameters, as well as on the expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP were studied in the hippocampus of 3xTg-AD mice. Treatment with the TNFSF10 neutralizing antibody resulted in dramatic improvement of cognitive parameters, as assessed by the Morris water maze test and the novel object recognition test. These results were correlated with decreased protein expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP in the hippocampus. Finally, neutralization of TNFSF10 results in functional improvement and restrained immune/inflammatory response in the brain of 3xTg-AD mice in vivo. Thus, it is plausible to regard the TNFSF10 system as a potential target for efficacious treatment of amyloid related disorders.