The relationship between β-amyloid (Aβ) and tau is not fully understood, though it is proposed that in the pathogenesis of Alzheimer's disease (AD) Aβ accumulation precedes and promotes tau hyperphosphorylation via activation of glycogen synthase kinase-3beta (GSK-3β). Both events contribute to learning and memory impairments. Modulation of γ-secretase activity has proved to reduce the Aβ burden and cognitive deficits in mouse models of AD, but its ability in reducing the tau pathology remains elusive. Chronic treatments with two γ-secretase modulators, ibuprofen and CHF5074, disclosed higher activity of CHF5074 in ameliorating brain plaque deposition and spatial memory deficits in transgenic mice expressing human amyloid precursor protein (hAPP) with Swedish and London mutations (APP(SL) mice). The aim of our study was to investigate in APP(SL) mice the effect of the two compounds on the accumulation of native hyperphosphorylated tau as well as on the GSK-3β signaling. CHF5074 was more effective than ibuprofen in reducing tau pathology, though both compounds decreased the GSK-3β level and increased the GSK-3β inhibitory phosphorylation near to the non-Tg values. The inhibition of GSK-3β appeared to be secondary to the reduction of Aβ generation as, differently from LiCl, CHF5074 reproduced its effect in hAPP-overexpressing neuroglioma cells, but not in wild-type primary neurons. Our data show that the novel γ-secretase modulator CHF5074 can fully reverse β-amyloid-associated tau pathology, thus representing a promising therapeutic agent for AD.