Modern medicine has unveiled that essential oil made from Aquilaria possesses sedative and hypnotic effects. Among the chemical components in Aquilaria, nerolidol, a natural sesquiterpene alcohol, has shown promising effects. This study aimed to unravel the potential of nerolidol in treating depression. Chronic unpredictable mild stress (CUMS) was utilized to induce depression-like behavior in mice, and open field test, sucrose preference, and tail suspension test was conducted. The impacts of nerolidol on the inflammatory response, microglial activation, and DNA methyltransferase 1 (DNMT1) were assessed. To study the regulatory role of DNMT1, lipopolysaccharide (LPS) was used to treat BV2 cells, followed by the evaluation of cell viability and DNMT1 level. Additionally, the influence of DNMT1 overexpression on BV2 cell activation was determined. Behavioral analysis revealed that nerolidol reduced depression-like behavior in mice. Nerolidol reduced the levels of inflammatory factors and microglial activation caused by CUMS. Nerolidol treatment was found to reduce DNMT1 levels in mouse brain tissue and it also decrease the LPS-induced increase in DNMT1 levels in BV2 cells. DNMT1 overexpression reversed the impacts of nerolidol on the inflammation response and cell activation. This study underscores the potential of nerolidol in reducing CUMS-induced depressive-like behavior and inhibiting microglial activation by downregulating DNMT1. These findings offer valuable insights into the potential of nerolidol as a therapeutic option for depression.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.