Alzheimer’s disease (AD) is the most common form of dementia in the elderly without cure approaches. Increasing evidence indicates that the activation of p38 MAPK is highly expression in AD brain and involved in the AD pathological process. However, whether specific inhibition of p38α/β MAPK activation could prevent disease progression and its underlying mechanisms remains completely unclear. In this study we investigated the potential disease-modifying therapeutic effect and its underlying mechanisms of specific inhibition of p38α/β MAPK activation by SB239063, a potent and selective p38α/β MAPK specific inhibitor, in six-month-old male APPswe/PS1dE9 mice. Our results revealed that chronic treatment of SB239063 potently inhibited p38 MAPK activation, which led to a marked improvement of cognitive impairments, dramatic reduction in Aβ production, tau hyperphosphorylation and synaptic impairments in APPswe/PS1dE9 mice. In addition, SB239063 treatment strongly enhanced nonamyloidogenic APP processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression as well as inhibited tau phosphorylation kinase activation in APPswe/PS1dE9 mice. Collectively, this study demonstrates that chronic SB239063 treatment potently inhibits p38α/β MAPK activation, which prevents the disease progression by markedly attenuating multiple AD-associated key neuropathologies and cognitive dysfunction. Our findings provide novel insights of the mechanisms of inhibition of p38α/β MAPK activation for the treatment of AD and highlight that specific inhibition of p38α/β MAPK activation by SB239063 treatment may be a promising therapeutic strategy for AD treatment.