<p>The neurodegenerative illness Alzheimer’s disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO₂ NCs as an anti-Alzheimer’s disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO₂ NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO₂ NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer’s disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO₂ NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle’s ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO₂ NCs protected against cognitive and synaptic deficits in AlCl₃-induced AD rats (AlCl₃-AD). KMF@PEG-MnO₂ NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain’s levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO₂ NCs may serve as a promising therapeutic candidate for AD management.</p>