Background: Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. However, the underlying mechanisms of PSD remain ambiguous, and no objective diagnosis tool is available to diagnose PSD. Previous metabolomic studies on PSD included patients with ischemic and hemorrhagic stroke indiscriminately, which is not conducive to elucidating and predicting the occurrence of PSD. The aim of this study is to elucidate the pathogenesis of PSD and provide potential diagnostic markers for PSD in ischemic stroke patients.Methods: In total, 51 ischemic stroke patients at 2 weeks were included in this study. Those with depressive symptoms were assigned to the PSD group, while the others were assigned to the non-PSD group. Plasma metabolomics based on liquid chromatography-mass spectrometry (LC-MS) was performed to explore the differential plasma metabolites between the PSD and non-PSD groups.Results: Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial leastsquares discriminant analysis (OPLS-DA) showed significant metabolic alterations between PSD patients and non-PSD patients. In total, 41 differential metabolites were screened out, mainly including phosphatidylcholines (PCs), L-carnitine and acyl carnitines, succinic acid, pyruvic acid and L-lactic acid. Metabolite-related pathway analysis revealed that alanine, aspartate and glutamate metabolism, glycerophospholipid metabolism and the citrate cycle (TCA cycle) may contribute to the pathogenesis of PSD. A panel of three signature metabolites [PC(22:5(7Z,10Z,13Z,16Z,19Z)/15:0), LysoPA(18:1(9Z)/0:0) and 1,5-anhydrosorbitol] was determined as potential biomarkers for PSD in ischemic stroke patients.Conclusion: These findings are conducive to providing new insights into the pathogenesis of PSD and developing objective diagnostic tools for PSD in ischemic stroke patients.