Schistosomiasis, a chronic and debilitating parasitic disease, affects approximately 200 million people in the developing world and imposes a substantial public health and economic impact. Accurately diagnosing at the individual level, monitoring disease progression, and assessing the impact of pharmacological interventions at the population level are of prime importance for controlling schistosomiasis. Using a Schistosoma mansoni-mouse model, we present a characterization of a parasitic infection by metabolic profiling, employing (1)H NMR spectroscopy and multivariate pattern recognition techniques. We infected 10 mice with 80 S. mansoni cercariae each and collected urine samples 49 and 56 days postinfection. Urine samples were also obtained from 10 uninfected control mice at the same time. The metabolic signature of an S. mansoni infection consists of reduced levels of the tricarboxylic acid cycle intermediates, including citrate, succinate, and 2-oxoglutarate, and increased levels of pyruvate, suggesting stimulated glycolysis. A disturbance of amino acid metabolism was also associated with an S. mansoni infection, as indicated by depletion of taurine, 2-oxoisocaproate, and 2-oxoisovalerate and elevation of tryptophan in the urine. A range of microbial-related metabolites, i.e., trimethylamine, phenylacetylglycine, acetate, p-cresol glucuronide, butyrate, propionate, and hippurate, were also coupled with an S. mansoni infection, indicating disturbances in the gut microbiota. Our work highlights the potential of metabolic profiling to enhance our understanding of biological responses to parasitic infections. It also holds promise as a basis for novel diagnostic tests with high sensitivity and specificity and for improved disease surveillance and control.