Alzheimer's disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and, thus the primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, the design, synthesis, and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity are reported. The detailed studies establish TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies show the disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment shows a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrate rescued cognitive deficits. The excellent biocompatibility, blood–brain barrier permeability, and therapeutic efficacy to reduce the amyloid burden make TGR63 a promising candidate for the treatment of AD.