Alzheimer's disease is defined pathologically by the irregular buildup of senile plaques, neurofibrillary tangles, and associated neuroinflammation. As aging progresses, senescent cells gradually accumulate and significantly contribute to brain dysfunction; however, the precise mechanisms driving aging remain unclear. In the current study, ABT263, a potent senolytic drug, was administered orally to APP/PS1 mice (n = 16) for five days per cycle throughout the course of two cycles, and their behavioral tests in the Morris water maze were evaluated. Using mouse hippocampal tissue, senescence-related gene expression and SASP-associated protein expression were assessed using biochemical tests and immunohistochemical labeling. The Morris water maze test results indicated that ABT263 alleviated spatial memory impairment and reduced amyloid-β (Aβ) accumulation in APP/PS1 mice. Additionally, ABT263 treatment led to a decline in senescence-associated β-galactosidase activity, p16 senescence-related gene expression, and the expression of SASP-associated proteins, including IL-6, IL-8, and MMP-1. Further investigation revealed that ABT263 enhanced the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K) (Tyr458), serine/threonine kinase AKT (S473), and glycogen synthase kinase-3β (GSK-3β) (Ser9) in APP/PS1 mice. Our results showed that ABT263 protected neurons against Aβ pathology, reduced the accumulation of senescent cells, and improved cognitive decline by enhancing PI3K/AKT/GSK-3 activity.