Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory and cognitive deficits. Both amyloid β (Aβ) deposition and inflammatory response occur in the early course of AD, but the progression of cognitive impairment and its relationship with Aβ and neuroinflammation have not been fully understood. Dieckol is a phenolic compound from brown algae and has been reported to possess several health benefits. In particular, our previous studies have shown that the compound exerts the neuroprotective effects by inhibiting amyloidogenesis, oxidative stress and inflammatory responses against Aβ injury in cellular system. The aim of the present study was to demonstrate the cognitive improvement effect of dieckol via multiple mechanisms in AD mouse model. Human Aβ1-42 peptide was injected into the hippocampal CA1 region of mouse brains, followed by administration of dieckol (100 mg/kg/day) for 3 weeks, and histological changes and neuroprotective effect of dieckol were evaluated. Immunostaining showed that Aβ injection dramatically increased Aβ plaques compared to the vehicle injection, while administration of dieckol after Aβ injection decreased Aβ burden through Akt/GSK-3β/Nrf2 regulated amyloidogenic pathway. Dieckol suppressed neuroinflammatory responses in the Aβ group as evidenced by lower tissue levels of IL-1β, GFAP, and iNOS, except for COX-2. Moreover, the compound inhibited both nuclear translocation of NF-kB p65 subunit and IkBα phosphorylation, which significantly attenuated Aβ-mediated cognitive and memory dysfunction. Overall, the present study provided a novel insight into feasibility of developing the compound as a neuroprotective agent for AD.