Microtus fortis (M. fortis) is the only mammal known in China that is intrinsically resistant to Schistosoma japonicum (S. japonicum) infection. Nevertheless, the underlying resistance mechanism of M. fortis against schistosomes are still unclear. In this study, we detected and compared colon aqueous extracts and serum metabolic profiles between M. fortis and ICR mice before and after S. japonicum infection using liquid chromatography-mass spectrometry (LC-MS). We identified 232 specific colon aqueous extract metabolites and 79 specific serum metabolites of M. fortis infected with or without S. japonicum at two weeks compared with those of ICR mice, which might be closely correlated with the time-course of schistosomiasis progression and could also be used as indicators for the M. fortis against S. japonicum, for example, nonadecanoic acid, hesperetin, glycocholic acid, 2-Aminobenzoic acid, 6-hydroxydaidzein and spermidine. And the enriched pathways were further identified, our findings revealed that S. japonicum infection induced the metabolic changes involved in a variety of metabolic pathways including amino acid metabolism, lipid metabolism, ABC transporters, central carbon metabolism in cancer and bile secretion. These results indicated that the colon aqueous extracts and serum metabolic profiles were significantly different between M. fortis and ICR mice before and after S. japonicum infection and will provide new insights into the underlying resistance mechanism of M. fortis against S. japonicum infection and identify promising candidates for the use of drugs against schistosomes.