‘Omics’ and bioinformatics were used to identify unique signatures characterizing liver of cows with postpartal ketosis relative to healthy cows fed rumen-protected methionine during late-pregnancy. Transcriptomics and metabolomics data were generated from liver tissue (n = 8/group, d −10 relative to parturition) of cows overfed a higher-energy diet during the dry period and classified as follows based on postpartal health: healthy (OVE), ketosis (K), or OVE plus Smartamine M (SM) or MetaSmart (MS). Data integration was via Ingenuity Pathways Analysis. Network construction included transcription regulators (TR) within the transcriptomics database and metabolites obtained through GC/MS-LC/MS. By comparing the different groups we obtained 21, 6, 10, 3, 11 and 15 transcription regulators (TR) out of 2908, 832, 1261, 922, 1573 and 1033, respectively, differentially expressed genes from K vs. OVE, K vs. SM, K vs. MS, SM vs. OVE, MS vs. OVE and SM vs. MS. Out of 313 known biochemical compounds, we detected 25, 34, 33, 20, 21, and 48 affected metabolites in the respective comparisons. As an example, using the TR (HIF1A, HIF3A, SIRT1, HDAC4) along with affected metabolites (cholic acid, D-erythro-dihydrosphingosine, lactic acid, malic acid, xylitol) in K vs. OVE the bioinformatics analyses revealed alterations in pathways related to tissue growth, and glucose and lipid metabolism. In regards to the methionine-supplemented groups, using the TR (HDAC2, SOX10, STAT1) along with affected metabolites (arginine, inosine) in SM vs. OVE the bioinformatics analyses revealed alterations in pathways related to regulation of liver regeneration and metabolism. Unique patterns also were detected between SM and MS, analysis of the TR (CREBBP, GATA2, NFKB2, STAT1) along with affected metabolites (arachidonic acid, arginine, chenodeoxycholic acid, docosahexaenoic acid, oleic acid) revealed alterations in pathways involved in cell signaling, immune response, and cholesterol synthesis. Results indicate that ‘omics’ data integration could be helpful in better understanding the link between nutrition and incidence of disorders after calving.