Salmonella Typhimurium is a bacterial pathogen that poses a great threat to humans and animals. In order to discover host's responses to S. Typhimurium infection, we collected and analyzed the biofluids and organ tissues from mice which had ingested S. Typhimurium. We employed 1H NMR spectroscopy coupled with multivariate data analysis and immunological techniques. The results indicate that infection leads to a severe impact on mice spleen and ileum, which are characterized by splenomegaly and edematous villi respectively. We found that increased levels of itaconic acid, which correlates with the presence of splenomegaly during infection and may play an important role in Salmonella-containing vacuole (SCV) acidification. In addition, metabonomic analyses of urine displays the development of salmonellosis in mice, which is characterized by dynamic changes in energy metabolism. Furthermore, we found that the presence of S. Typhimurium activated an anti-oxidative response in infected mice. We also observed the changes of gut microbial co-metabolites (hippurate, TMAO, TMA, methylamine). The investigation sheds much needed light on the host-pathogen interactions of S. Typhimurium, which provides further information for deepening our understanding of the long co-evolution process between hosts and infective bacteria.