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This study aims to assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. The MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435C>T, and GSTP1 313A>G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC–MS). The results of univariate and multivariate analyses showed that MTHFR 677C>T and ABCB1 3435 C>T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No significant association was identified between MTHFR 677C>T, MTHFR 1298A>C, ABCB1 3435 C>T, and GSTP1 313A>G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by influencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects. Conclusion: MTHFR 677C>T and ABCB1 3435 C>T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were significantly elevated after HD-MTX treatment in children with the MTHFR 677C>T mutation gene. Trial registration: This study was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2000035264; registration: 2020/08/05; https://www.chictr.org.cn/). What is Known: • MTX-related genes play an important role in MTX pharmacokinetics and toxicity, but results from different studies are inconsistent and the mechanisms involved are not clear. What is New: • Characteristics, prognosis, polymorphisms of MTX-related genes, and metabolite changes were comprehensively evaluated in children treated with HD-MTX chemotherapy. • Analysis revealed that both heterozygous and pure mutations in MTHFR 677C>T resulted in a significantly increased risk of delayed MTX clearance, and that L-phenylalanine has the potential to serve as a predictive marker for the metabolic effects of the MTHFR 677C>T polymorphism. [ABSTRACT FROM AUTHOR]