Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. l-3-n-butylphthalide (l-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been demonstrated to have neuroprotective effects on ischemic, vascular dementia, and amyloid-β (Aβ)-infused animal models. In the current study, we examined the effects of l-NBP on learning and memory in a triple-transgenic AD mouse model (3xTg-AD) that develops both plaques and tangles with aging, as well as cognitive deficits. Ten-month-old 3xTg-AD mice were given 15 mg/kg l-NBP by oral gavage for 18 weeks. l-NBP treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. l-NBP treatment significantly reduced total cerebral Aβ plaque deposition and lowered Aβ levels in brain homogenates but had no effect on fibrillar Aβ plaques, suggesting preferential removal of diffuse Aβ deposits. Furthermore, we found that l-NBP markedly enhanced soluble amyloid precursor protein secretion (αAPPs), α-secretase, and PKCα expression but had no effect on steady-state full-length APP. Thus, l-NBP may direct APP processing toward a non-amyloidogenic pathway and preclude Aβ formation in the 3xTg-AD mice. The effect of l-NBP on regulating APP processing was further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP695 (SK-N-SH APPwt). l-NBP treatment in 3xTg-AD mice also reduced glial activation and oxidative stress compared with control treatment. l-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer's disease.