Icariin is derived most commonly from the traditional Chinese herb Epimedium brevicornum Maxim. Our previous studies have shown that icariin protects neurons from neurotoxic and ischemic conditions. This study aims to investigate the effect of icariin on the expression of amyloid precursor protein (APP) and the level of amyloid-β peptide (Aβ), as well as neurogenesis in the brain of Tg2576 mice, an animal model of Alzheimer's disease (AD). Tg2576 mice and wild-type littermates (WT) were randomized into the following three groups: Tg2576, Tg2576+icariin, and WT groups. All 9-month-old mice were treated with icariin (60mg/kg/d) or distilled water for 3months. Following this, the spatial working memory of Tg2576+icariin mice, as examined in the Y-maze task, was found to improve. Furthermore, reduced levels of insoluble Aβ1-40 (69%) and Aβ1-42 (50%) after icariin treatment were determined in the brain by enzyme-linked immunosorbent assay (ELISA). Western blot analysis indicated the downregulation of APP expression after icariin treatment, and double staining showed an increased number of 5-bromo-2-deoxyuridine (BrdU)/Neuron-specific nuclear protein (NeuN) double-positive cells in the dentate gyrus region of the hippocampus in Tg2576+icariin mice compared with the Tg2576 mice. The current study demonstrated that icariin improved memory function, decreased the levels of Aβ and APP in the brain, and enhanced neurogenesis in the hippocampus of Tg2576 mice. Collectively, these results suggest the potential therapeutic value of icariin in AD.