Transcriptomic and metabonomic methods were used to investigate mice's responses to drinking source water (DSW) exposure. After mice were fed with DSW for 90 days, hepatic transcriptome was characterized by microarray and serum metabonome were determined by (1)H nuclear magnetic resonance (NMR) spectroscopy. A total of 243 differentially expressed genes (DEGs) were identified, among which 141 genes were up-regulated and 102 genes were down-regulated. Metabonomics revealed significant changes in concentrations of creatine, pyruvate, glutamine, lysine, choline, acetate, lipids, taurine, and trimethylamine oxide. Four biological pathways were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis where both gene expression and metabolite concentrations were altered in response to DSW exposure. These results highlight the significance of combined use of transcriptomic and metabonomic approaches in evaluating potential health risk induced by DSW contaminated with various hazardous materials.