This study examined the effects of ibuprofen on cognitive deficits, Aβ and tau accumulation in young triple transgenic (3×Tg-AD) mice. 3×Tg-AD mice were fed ibuprofen-supplemented chow between 1 and 6 months. Untreated 3×Tg-AD mice showed significant impairment in the ability to learn the Morris water maze (MWM) task compared to age-matched wild-type (WT) mice. The performance of 3×TgAD mice was significantly improved with ibuprofen treatment compared to untreated 3×Tg-AD mice. Ibuprofen-treated transgenic mice showed a significant decrease in intraneuronal oligomeric Aβ and hyperphosphorylated tau (AT8) immunoreactivity in the hippocampus. Confocal microscopy demonstrated co-localization of conformationally altered (MC1) and early phosphorylated tau (CP-13) with oligomeric Aβ, and less co-localization of oligomeric Aβ and later forms of phosphorylated tau (AT8 and PHF-1) in untreated 3×Tg-AD mice. These findings show that prophylactic treatment of young 3×Tg-AD mice with ibuprofen reduces intraneuronal oligomeric Aβ, reduces cognitive deficits, and prevents hyperphosphorylated tau immunoreactivity. These findings provide further support for intraneuronal Aβ as a cause of cognitive impairment, and suggest that pathological alterations of tau are associated with intraneuronal oligomeric Aβ accumulation.