The metabotropic glutamate receptor 5 (mGluR5) is widely expressed in postsynaptic neurons and plays a vital role in the synaptic plasticity of the central nervous system. mGluR5 is a coreceptor for amyloid-β (Aβ) oligomer, and downregulation or pharmacological blockade of mGluR5 presents the therapeutic potential of Alzheimer's disease (AD). However, the abnormality of mGluR5 in the pathogenesis of AD and its mechanism of pathology is not clear.In this study, we would like to investigate the expression of mGluR5 in the process of AD and explore the effects and the underlying mechanisms of antagonizing mGluR5 on cognitive function, synaptic structure, and inflammation in 5xFAD mice.mGluR5 expression and interactions with PrPc in 5XFAD mice were detected using western blot and co-immunoprecipitation. The selective mGluR5 antagonist MPEP was infused into 4-month-old 5XFAD mice for 60 consecutive days. Then, cognitive function, AD-like pathology and synaptic structure were measured. Further observations were made in mGluR5 knockdown 5XFAD mice.mGluR5 expression was increased with Aβ levels at 6 months in 5XFAD mice. mGluR5 antagonist rescued cognitive disorders, promoted synaptic recovery, and alleviated both the Aβ plaque load and abnormal hyperphosphorylation in 6-month-old 5XFAD mice. Meanwhile, the results were validated in mGluR5 knockdown mice. Blockade of mGluR5 efficiently alleviates AD-like pathologies by inhibiting the PI3K/AKT/mTOR pathway and activates autophagy in 5XFAD mice. Furthermore, antagonism of mGluR5 attenuated neuroinflammation by inactivating the IKK/NF-κB pathway.These findings suggest that mGluR5 may be an effective drug target for AD treatment, and inhibition of the mGluR5/PI3K-AKT pathway alleviates AD-like pathology by activating autophagy and anti-neuroinflammation in 5XFAD mice.