The neurotoxicity of Aβ peptides has been well documented, but effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we investigated effects of 1-Methylnicotinamide (MNA), known as a main metabolite of nicotinamide (NA), on the impairment of learning and memory induced by Aβ and the underlying mechanisms. We found that intragastric administration of MNA at 100 or 200 mg/kg for 3 weeks significantly reversed bilateral intrahippocampal injection of Aβ1-42-induced cognitive impairments in the Morris water maze (MWM), Y-maze and Novel object recognition tests. Furthermore, MNA suppressed Aβ1-42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the expression of IL-6, TNF-α and nuclear translocation of NF-κB p65, as well as attenuated neuronal apoptosis as indicated by decreased TUNEL-positive cells and ratio of caspase-3 fragment to procaspase-3, and increased ratio of Bcl-2/Bax in the hippocampus. Our results show that MNA may ameliorate Aβ1-42-induced cognition deficits, which is involved in inhibition of neuroinflammation and apoptosis mediated by NF-κB signaling, suggesting that MNA could have potential therapeutic value for AD. Graphical Abstract Neuroprotective affect of MNA on Aβ1-42-induced cognitive deficits.