Ischemia stroke is thought to be one of vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from CCK-8 showed that 10μM HSYA restored the cell viability after OGD 2 h/R 24 h. HSYA reduced the levels of malondialdehyde and ROS, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like ER kinase pathway and activating transcription factor 6 pathway, while the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving endoplasmic reticulum stress.