: The current staging of non-small cell lung cancer (NSCLC) relies on conventional imaging, which lacks the sensitivity to detect micrometastatic disease. The functional assessment of NSCLC progression may provide independent information to enhance the prediction of metastatic risk. The objective of this study was to determine if we could identify a metabolomic signature predictive of metastasis in patients with NSCLC treated with definitive radiation. : Plasma samples were collected prospectively from patients enrolled in a clinical trial with non-metastatic NSCLC treated with definitive radiation. Metabolites were extracted, and mass spectrometry-based analysis was performed using a flow injection electrospray (FIE)-Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) method. Early metastasis was defined as metastasis within 1 year of radiation treatment. : The study cohort included 28 patients. FIE-FITCR produced highly reproducible profiles in technical replicates. A total of 51 metabolic features were identified to be different in patients with early metastasis compared to patients without early metastasis (all adjusted -values < 0.05, Welch's -test), including glycerophospholipids, sphingolipids, and fatty acyls. In the follow-up samples collected after the initiation of chemotherapy and radiation treatment, a total of 174 metabolic features were significantly altered in patients who developed early metastasis compared to those who did not. : We identified several distinct changes in the metabolic profiles of patients with NSCLC who developed metastatic disease within 1 year of definitive radiation. These findings highlight the potential of metabolomic profiling as a predictive tool for assessing metastatic risk in NSCLC.