Amyloid plaques and neurofibrillaric tangles are pathological characteristics of Alzheimer’s disease (AD). Endoplasmic reticulum stress (ERS) is involved in the neuron loss of AD. The aim of this study is to improve the amyloid plaques in an AD mouse model using Hei-Xiao-Yao-San (HXYS), a Chinese traditional medical formula. A mouse AD model was established. AD mice (APP/PS1 mice) were treated with HXYS or saline. Cognitive function in mice was evaluated by using the Morris water maze. The histology of the hippocampus was evaluated by hematoxylin eosin (H&E) staining. The ultra-structure of the hippocampal tissue was observed under a transmission electron microscope.Treatment with HXYS significantly enhanced cognitive function in AD mice. Neural loss and synaptic plasticity of the hippocampus were significantly improved. The amounts of APP (amyloid-beta precursor protein) and ERS associated proteins (CHOP and PERK) in the hippocampus were significantly reduced in AD mice. HXYS may enhance cognitive function in AD mice by regulating ERS.