Purpose: This study aims to evaluate the value of a serum metabolomics-based metabolic signature for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients, thereby assisting clinical decisions. Methods: In this retrospective study, a total of 320 LA-NPC patients were randomly divided into a training set (ca. 70%;n= 224) and a validation set (ca. 30%;n= 96). Serum samples were analyzed using widely targeted metabolomics. Univariate and multivariate Cox regression analyses were used to identify candidate metabolites related to progression-free survival (PFS). Patients were categorized into high-risk and low-risk groups based on the median metabolic risk score (Met score), and the PFS difference between the two groups was compared using Kaplan–Meier curves. The predictive performance of the metabolic signature was evaluated using the concordance index (C-index) and the time-dependent receiver operating characteristic (ROC), and a comprehensive nomogram was constructed using the Met score and other clinical factors. Results: Nine metabolites were screened to build the metabolic signature and generate the Met score, which effectively separated patients into low- and high-risk groups. The C-index in the training and validation sets was 0.71 and 0.73, respectively. The 5-year PFS was 53.7% (95% CI, 45.12–63.86) in the high-risk group and 83.0% (95%CI, 76.31–90.26) in the low-risk group. During the construction of the nomogram, Met score, clinical stage, pre-treatment EBV DNA level, and gender were identified as independent prognostic factors for PFS. The predictive performance of the comprehensive model was better than that of the traditional model. Conclusion: The metabolic signature developed through serum metabolomics is a reliable prognostic indicator of PFS in LA-NPC patients and has important clinical significance.