Background: Physical exercise has been shown to be beneficial for individuals with Alzheimer’s disease (AD), although the underlying mechanisms are not fully understood. Methods: Six-month-old Amyloid precursor protein/Presenilin 1 (APP/PS1) transgenic (Tg) mice and wild-type (Wt) mice were randomly assigned to either a sedentary group (Tg-Sed, Wt-Sed) or an exercise group (Tg-Ex, Wt-Ex) undertaking a 12-week, moderate-intensity treadmill running program. Consequently, all mice were tested for memory function and amyloid \beta (A\beta) levels and phosphorylation of tau and protein kinase B (Akt)/glycogen synthase kinase-3 (GSK3) were examined in tissues of both the cortex and hippocampus. Results: Tg-Sed mice had severely impaired memory, higher levels of A\beta, and increased phosphorylation of tau, GSK3\alpha tyrosine279, and GSK3\beta tyrosine216, but less phosphorylation of GSK3\alpha serine21, GSK3\beta serine9, and Akt serine473 in both tissues than Wt-Sed mice in respective tissues. Tg-Ex mice showed significant improvement in memory function along with lower levels of A\beta and less phosphorylation of tau (both tissues), GSK3\alpha tyrosine279 (both tissues), and GSK3\beta tyrosine216 (hippocampus only), but increased phosphorylation of GSK3\alpha serine21 (both tissues), GSK3\beta serine9 (hippocampus only), and Akt serine473 (both tissues) compared with Tg-Sed mice in respective tissues. Conclusions: Moderate-intensity aerobic exercise is highly effective in improving memory function in 9-month-old APP/PS1 mice, most likely through differential modulation of GSK3\alpha/\beta phosphorylation in the cortex and hippocampus.