Paeoniflorin, the main active component of the peony plant, exerts various pharmacological effects. Recently, research on the effect of paeoniflorin on the nervous system has gained more attention. The aim of the present study was to determine whether paeoniflorin exerts a protective effect that improves Alzheimer's disease (AD) via inflammation and apoptosis in the cerebral cortex of a transgenic mouse model of AD. Transgenic mice were used to construct the model of AD and were treated with paeoniflorin. The Morris water maze test was used to analyze cognitive function in AD mice. The protein expression levels of nuclear factor‑κB, tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and caspase‑3 were examined with commercial kits. Expression levels of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), phosphorylated (p)‑Akt and p‑p38 mitogen‑activated protein kinase (p‑p38 MAPK) in AD were evaluated by western blotting. The neuroprotective effects of paeoniflorin significantly improved cognitive function and ameliorated patterns of escape distance and escape latency in AD mice. Furthermore, the effects of paeoniflorin decreased inflammation and caspase‑3 activity, and inhibited cell death via increasing the Bcl‑2/Bax ratio and p‑Akt expression levels, and downregulating p‑p38 MAPK expression in AD mice.