Acute coronary syndrome (ACS) is an emergency and severe disorder of the cardiovascular system. This paper assessed the expression of plasma HAND2-AS1 in patients with ACS, researched its diagnostic and prognostic significance, and studied its possible mechanism for participating in ACS.The concentration of HAND2-AS1 of 101 included patients with ACS was certified by qRT-PCR and its possible diagnostic function was revealed by the receiver operating characteristic (ROC) curve. All patients were followed up for 6 months after percutaneous coronary intervention (PCI) therapy and Kaplan-Meier (K-M) curve and COX regression analysis was performed to estimate the short-term prognostic value of HAND2-AS1 in ACS. The interrelationship between HAND2-AS1 and Gensini score and endothelial injury was identified via Pearson correlation. The function of HAND2-AS1 on the viability, migration, and apoptosis of human umbilical vein endothelial cells (HUVECs) was estimated by the Cell Counting Kit-8 (CCK-8), Transwell chamber, and flow cytometry.In ACS patients, the expression of serum HAND2-AS1 was prominently decreased and closely correlated with the Gensini score. The decreased HAND2-AS1 expression was of diagnostic significance. Declined plasma HAND2-AS1 was observed in patients with the major adverse cardio-cerebrovascular event (MACCE) and was an independent risk for the poor prognosis of ACS patients. In the cell model, upregulation of HAND2-AS1 improved cell viability and migration and inhibited cell apoptosis.HAND2-AS1 was an independent biomarker for the diagnosis and prognosis of ACS. HAND2-AS1 might be involved in ACS development by regulating endothelial damage.© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.