This study was to investigate the effects of Toll-like receptor-3 (TLR3) activation on cognitive impairment and neuropathology in late-stage of Alzheimer's disease in a mouse model. Amyloid protein precursor (APP)/presenilin-1 (PSEN1) (APP/PSEN1) mice were treated with Poly (I:C), a specific for TLR3. A panel of neurobehavioral tests were conducted to evaluate their cognitive functions. Aβ deposition, plasma Aβ levels, neuropathological changes, and activation of TLR3- TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling were assessed by magnetic resonance imaging (MRI), electrophysiological recordings, transmission electron microscopy, Western blotting, immunofluorescence staining, and qPCR. The data demonstrated that Poly (I:C) significantly attenuated cognitive and neuropathological impairments, compared with APP/PSEN1 mice without Poly (I:C) treatment. Administration of Poly (I:C) significantly reduced brain Aβ deposition and the levels of Aβ and Aβ in peripheral blood. In addition, treatment with Poly (I:C) significantly up-regulated the expression of anti-inflammatory factors and inhibited the expression of pro-inflammatory factors. The data indicated that systemic application of TLR3 agonist Poly(I:C) attenuated the brain damage, improved the cognitive function, and reduced the levels of Aβ in brain and peripheral blood. The underlying mechanism might attribute to the up-regulation of p-IRF3 that increases the expression of anti-inflammatory factors and the inhibition of p-NF-κB that reduces the expression of pro-inflammatory factors.