Early diagnosis and therapeutic interventions can greatly enhance the developmental trajectory of children with autism spectrum disorder (ASD). However, the etiology of ASD is not completely understood. The presence of confounding factors from environment and genetics has increased the difficulty of the identification of diagnostic biomarkers for ASD.To estimate and interpret the causal relationship between ASD and metabolite profile, taking into consideration both genetic and environmental influences.A two-sample Mendelian randomization (MR) analysis was conducted using summarized data from large-scale genome-wide association studies (GWAS) including a metabolite GWAS dataset covering 453 metabolites from 7824 European and an ASD GWAS dataset comprising 18381 ASD cases and 27969 healthy controls. Metabolites in plasma were set as exposures with ASD as the main outcome. The causal relationships were estimated using the inverse variant weight (IVW) algorithm. We also performed leave-one-out sensitivity tests to validate the robustness of the results. Based on the drafted metabolites, enrichment analysis was conducted to interpret the association via constructing a protein-protein interaction network with multi-scale evidence from databases including Infinome, SwissTargetPrediction, STRING, and Metascape.Des-Arg(9)-bradykinin was identified as a causal metabolite that increases the risk of ASD (β = 0.262, SE = 0.064, PIVW = 4.64 × 10-5). The association was robust, with no significant heterogeneity among instrument variables (PMR Egger = 0.663, PIVW = 0.906) and no evidence of pleiotropy (P = 0.949). Neuroinflammation and the response to stimulus were suggested as potential biological processes mediating the association between Des-Arg(9) bradykinin and ASD.Through the application of MR, this study provides practical insights into the potential causal association between plasma metabolites and ASD. These findings offer perspectives for the discovery of diagnostic or predictive biomarkers to support clinical practice in treating ASD.©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.