This research aims to investigate whether soybean isoflavone (SIF) could alleviate the learning and memory deficit induced by β-amyloid peptides 1-42 (Aβ1-42) by protecting the synapses of rats. Adult male Wistar rats were randomly allocated to the following groups: (1) control group; (2) Aβ1-42 group; (3) SIF group; (4) SIF + Aβ1-42 group (SIF pretreatment group) according to body weight. The 80 mg/kg/day of SIF was administered orally by gavage to the rats in SIF and SIF+Aβ1-42 groups. Aβ1-42 was injected into the lateral cerebral ventricle of rats in Aβ1-42 and SIF+Aβ1-42 groups. The ability of learning and memory, ultramicrostructure of hippocampal synapses, and expression of synaptic related proteins were investigated. The Morris water maze results showed the escape latency and total distance were decreased in the rats of SIF pretreatment group compared to the rats in Aβ1-42 group. Furthermore, SIF pretreatment could alleviate the synaptic structural damage and antagonize the down-regulation expressions of below proteins induced by Aβ1-42: (1) mRNA and protein of the synaptophysin and postsynaptic density protein 95 (PSD-95); (2) protein of calmodulin (CaM), Ca2+/calmodulin-dependent protein kinase II (CaMK II), and cAMP response element binding protein (CREB); (3) phosphorylation levels of CaMK II and CREB (pCAMK II, pCREB). These results suggested that SIF pretreatment could ameliorate the impairment of learning and memory ability in rats induced by Aβ1-42, and its mechanism might be associated with the protection of synaptic plasticity by improving the synaptic structure and regulating the synaptic related proteins. Synapse 67:856–864, 2013. © 2013 Wiley Periodicals, Inc.