Alzheimer＇s　disease　(AD)　is　a　neurodegenerative　disease　associated　with　amyloid-β　(Aβ)　deposition,　leading　to　neurotoxicity　(oxidative　stress　and　neuroinflammation)　and　gut　microbiota　imbalance.　Resveratrol　(Res)　has　neuroprotective　properties,　but　its　bioavailability　in　vivo　is　very　low.　Herein,　we　developed　a　small　Res-selenium-peptide　nanocomposite　to　enable　the　application　of　Res　for　eliminating　Aβ　aggregate-induced　neurotoxicity　and　mitigating　gut　microbiota　disorder　in　aluminum　chloride　(AlCl3)　and　d-galactose(d-gal)-induced　AD　model　mice.　Res　functional　selenium　nanoparticles　(Res@SeNPs)　(8　±　0.34　nm)　were　prepared　first,　after　which　the　surface　of　Res@SeNPs　was　decorated　with　a　blood-brain　barrier　transport　peptide　(TGN　peptide)　to　generate　Res-selenium-peptide　nanocomposites　(TGN-Res@SeNPs)　(14　±　0.12　nm).　Oral　administration　of　TGN-Res@SeNPs　improves　cognitive　disorder　through　(1)　interacting　with　Aβ　and　decreasing　Aβ　aggregation,　effectively　inhibiting　Aβ　deposition　in　the　hippocampus;　(2)　decreasing　Aβ-induced　reactive　oxygen　species　(ROS)　and　increasing　activity　of　antioxidation　enzymes　in　PC12　cells　and　in　vivo;　(3)　down-regulating　Aβ-induced　neuroinflammation　via　the　nuclear　factor　kappa　B/mitogen-activated　protein　kinase/Akt　signal　pathway　in　BV-2　cells　and　in　vivo;　and　(4)　alleviating　gut　microbiota　disorder,　particularly　with　respect　to　oxidative　stress　and　inflammatory-related　bacteria　such　as　Alistipes,　Helicobacter,　Rikenella,　Desulfovibrio,　and　Faecalibaculum.　Thus,　we　anticipate　that　Res-selenium-peptide　nanocomposites　will　offer　a　new　potential　strategy　for　the　treatment　of　AD.　©　2021　American　Chemical　Society.