Purpose Metabolic phenotyping has provided important biomarker findings, which, unfortunately, are rarely replicated across different sample sets due to the variations from different analytical and clinical protocols used in the studies. To date, very few metabolic hallmarks in a given cancer type have been confirmed and validated by use of a metabolomic approach and other clinical modalities. Here, we report a metabolomics study to identify potential metabolite biomarkers of colorectal cancer with potential theranostic value. Experimental Design Gas chromatography–time-of-flight mass spectrometry (GC–TOFMS)–based metabolomics was used to analyze 376 surgical specimens, which were collected from four independent cohorts of patients with colorectal cancer at three hospitals located in China and City of Hope Comprehensive Cancer Center in the United States. Differential metabolites were identified and evaluated as potential prognostic markers. A targeted transcriptomic analysis of 29 colorectal cancer and 27 adjacent nontumor tissues was applied to analyze the gene expression levels for key enzymes associated with these shared metabolites. Results A panel of 15 significantly altered metabolites was identified, which demonstrates the ability to predict the rate of recurrence and survival for patients after surgery and chemotherapy. The targeted transcriptomic analysis suggests that the differential expression of these metabolites is due to robust metabolic adaptations in cancer cells to increased oxidative stress as well as demand for energy, and macromolecular substrates for cell growth and proliferation. Conclusions These patients with colorectal cancer, despite their varied genetic background, mutations, pathologic stages, and geographic locations, shared a metabolic signature that is of great prognostic and therapeutic potential.