On a global scale, lung cancer(LC) is the most commonly occurring form of cancer. Nonetheless, the process of screening and detecting it in its early stages presents significant challenges. Earlier research endeavors have recognized metabolites as potentially reliable biomarkers for LC. However, the majority of these studies have been limited in scope, featuring inconsistencies in terms of the relationships and levels of association observed.Moreover, there has been a lack of consistency in the types of biological samples utilized in previous studies. Therefore, the main objective of our research was to explore the correlation between metabolites and Non-small cell lung cancer (NSCLC).Thorough two-sample Mendelian randomization (TSMR) analysis, we investigated potential cause-and-effect relationships between 1400 metabolites and the risk of NSCLC.The analysis of TSMR revealed a significant causal impact of 61 metabolites on NSCLC.To ensure the reliability and validity of our findings, we perform FDR correction for P-values by Benjaminiand Hochberg(BH) method, Our results indicate that Oleate/vaccenate (18:1) levels and Caffeine to paraxanthine ratio may be causally associated with an increased risk of NSCLC [Oleate/vaccenate(18:1)levels: OR = 1.171,95%CI: 1.085-1.265, FDR = 0.036; Caffeine to paraxanthine ratio: OR = 1.386, 95%CI:1.191-1.612,FDR = 0.032].Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.