Fructus　Psoraleae　(FP)　is　commonly　used　in　the　treatment　of　vitiligo,　osteoporosis,　and　other　diseases　in　clinic.　As　a　result,　the　toxicity　caused　by　FP　is　frequently　encountered　in　clinical　practice;　however,　the　underlying　toxicity　mechanism　remains　unclear.　The　purpose　of　this　study　was　to　investigate　the　toxic　effect　of　the　ethanol　extract　of　FP　(EEFP)　in　rats　and　to　explore　the　underlying　toxic　mechanisms　using　a　metabolomics　approach.　The　toxicity　was　evaluated　by　hematological　indicators,　biochemical　indicators,　and　histological　changes.　In　addition,　a　serum　metabolomic　method　based　on　ultra-performance　liquid　chromatography　coupled　with　quadrupole　time-of-flight　MS　(UPLC-Q-TOF-MS)　had　been　established　to　investigate　the　hepatorenal　toxicity　of　FP.　Multivariate　statistical　approaches,　such　as　partial　least　squares　discriminant　analysis　and　orthogonal　partial　least　squares　discriminant　analysis,　were　built　to　evaluate　the　toxic　effects　of　FP　and　find　potential　biomarkers　and　metabolic　pathways.　Ten　endogenous　metabolites　had　been　identified　and　the　related　metabolic　pathways　were　involved　in　phospholipid　metabolism,　amino　acid　metabolism,　purine　metabolism,　and　antioxidant　system　activities.　The　results　showed　that　long-term　exposure　to　high-dose　EEFP　may　cause　hepatorenal　toxicity　in　rats.　Therefore,　serum　metabolomics　can　improve　the　diagnostic　efficiency　of　FP　toxicity　and　make　it　more　accurate　and　comprehensive.