The goal of this study was to determine if acute treatment with the gamma secretase inhibitor DAPT improved the impaired hippocampal function exhibited by young (20 weeks) and older (65 weeks) Tg2576 mice. Acute treatment before training (but not after training or before testing) with the γ-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of β-amyloid (100 mg/kg), resulted in improved contextual memory in Tg2576 mice. At 20 weeks, a significant main effect of genotype (F(1,29) = 8.588; p < 0.05) was observed; however, neither the treatment main effect (F(1,29) = 1.213) nor the interaction (F(1,29) = 3.278) were significant. Vehicle-treated Tg2576 mice displayed no contextual conditioning and had memory scores significantly different from those observed in vehicle-treated controls (p< 0.05). In contrast, DAPT-treated (100 mg/kg) Tg2576 mice had memory scores that were not significantly different from those observed in the 20-week-old DAPT-treated controls (p = 0.4124) and displayed a significant increase relative to vehicle-treated Tg2576 mice (p < 0.05). In 36- and 54-week-old mice, significant group-by-treatment interactions were observed (36-week-old, F(1,28) = 5.751, p < 0.05; 54-week-old, F(1,26) = 4.465, p < 0.05). At both ages, DAPT-treated Tg2576 mice displayed significantly greater contextual memory than vehicle-treated Tg2576 mice (p < 0.05) and were not significantly different from DAPT-treated controls. In 65-week-old mice, as a result of animal availability, vehicle-treated Tg2576 were not tested. No significant difference was observed between control and Tg2576 mice treated with DAPT (F(1,18) = 1.212). No effect of DAPT was observed in controls at any age. An oral dose of 100 mg/kg of DAPT in Tg2576 mice resulted in reductions in brain levels of Aβ40 (F(6,48) = 10.912; p < 0.0001) and Aβ42 (F(6,48) = 3.706; p < 0.005). Significant reductions were observed in Aβ40 1–8 h and Aβ42 4–8 h after dosing relative to vehicle-treated Tg2576 mice. Levels of Aβ were no longer reduced 24 h after drug administration. These data support a role of β-amyloid in the hippocampal impairment in Tg2576 mic and, suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.