Colorectal cancer (CRC) is one of the most common and deadly malignancies. Novel biomarkers for the diagnosis and prognosis of this disease must be identified. Besides, metabolism plays an essential role in the occurrence and development of CRC. This article aims to identify some critical prognosis-related metabolic genes (PRMGs) and construct a prognosis model of CRC patients for clinical use. We obtained the expression profiles of CRC from The Cancer Genome Atlas database (TCGA), then identified differentially expressed PRMGs by R and Perl software. Hub genes were filtered out by univariate Cox analysis and least absolute shrinkage and selection operator Cox analysis. We used functional enrichment analysis methods, such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, to identify involved signaling pathways of PRMGs. The nomogram predicted overall survival (OS). Calibration traces were used to evaluate the consistency between the actual and the predicted survival rate. Finally, a prognostic model was constructed based on six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK1, and ADCY5), and the risk score was an independent prognostic prognosticator. Genetic expression and risk score were significantly correlated with clinicopathologic characteristics of CRC. A nomogram based on the clinicopathological feature of CRC and risk score accurately predicted the OS of individual CRC cancer patients. We also validated the results in the independent colorectal cancer cohorts GSE39582 and GSE87211. Our study demonstrates that the risk score is an independent prognostic biomarker and is closely correlated with the malignant clinicopathological characteristics of CRC patients. We also determined some metabolic genes associated with the survival and clinical stage of CRC as potential biomarkers for CRC diagnosis and treatment.©2020 Miao et al.