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Rosa damascena is an ancient plant with significance in both medicine and perfumery that have a variety of therapeutic properties, including antidepressant, anti-anxiety, and anti-stress effects. Rose damascena essential oil (REO) has been used to treat depression, anxiety and other neurological related disorders in Iranian traditional medicine. However, its precise mechanism of action remains elusive. The aim of this study was to investigate the impact and mechanism underlying the influence of REO on chronic unpredictable mild stress (CUMS) rats. Gas chromatography-mass spectrometry (GC-MS) technique coupling was used to analyze of the components of REO. A CUMS rat model was replicated to assess the antidepressant effects of varying doses of REO. This assessment encompassed behavioral evaluations, biochemical index measurements, and hematoxylin-eosin staining. For a comprehensive analysis of hippocampal tissues, we employed transcriptomics and incorporated weighting coefficients by means of network pharmacology. These measures allowed us to explore differentially expressed genes and biofunctional pathways affected by REO in the context of depression treatment. Furthermore, GC-MS metabolomics was employed to assess metabolic profiles, while a joint analysis in Metscape facilitated the construction of a network elucidating the links between differentially expressed genes and metabolites, thereby elucidating potential relationships and clarifying key pathways regulated by REO. Finally, the expression of relevant proteins in the key pathways was determined through immunohistochemistry and Western blot analysis. Molecular docking was utilized to investigate the interactions between active components and key targets, thereby validating the experimental results. REO alleviated depressive-like behavior, significantly elevated levels of the neurotransmitter 5-hydroxytryptamine (5-HT), and reduced hippocampal neuronal damage in CUMS rats. This therapeutic effect may be associated with the modulation of the serotonergic synapse signaling pathway. Furthermore, REO rectified metabolic disturbances, primarily through the regulation of amino acid metabolic pathways. Joint analysis revealed five differentially expressed genes (EEF1A1 , LOC729197 , ATP8A2 , NDST4 , and GAD2), suggesting their potential in alleviating depressive symptoms by modulating the serotonergic synapse signaling pathway and tryptophan metabolism. REO also modulated the 5-HT 2 A-mediated extracellular regulated protein kinases-cAMP-response element binding protein-brain-derived neurotrophic factor (ERK-CREB-BDNF) pathway. In addition, molecular docking results indicated that citronellol, geraniol and (E,E)-farnesol in REO may serve as key active ingredients responsible for its antidepressant effects. This study is the first to report that REO can effectively alleviate CUMS-induced depression-like effects in rats. Additionally, the study offers a comprehensive understanding of its intricate antidepressant mechanism from a multi-omics and multi-level perspective. Our findings hold promise for the clinical application and further development of this essential oil. [Display omitted] • The antidepressant mechanism of action of Rosa damascena essential oil may involve the modulation of the serotonergic synapse signaling pathway, which regulates the expression relevant proteins in the ERK-CREB-BDNF pathway. • Joint transcriptomics and metabolomics analyses validated that Rosa damascena essential oil regulates the tryptophan metabolic pathway. • Rosa damascena essential oil ameliorates hippocampal neuronal damage induced by CUMS and modulates neurotransmitter levels. • The key active components in Rosa damascena essential oil responsible for its antidepressant effects may include citronellol, geraniol and (E,E)-farnesol. [ABSTRACT FROM AUTHOR]