The objective of this study was to examine the effects of fermented ammoniated condensed whey (FACW) supplementation on hepatic gene expression and plasma metabolites related to liver function and inflammation, and on liver triglyceride content (lvTG). Individually fed multiparous Holstein cows were blocked by calving date and randomly assigned to postpartum (1 to 45 d in milk, DIM) isonitrogenous treatments: control (CTL; n = 20) or FACW (2.9% DM of diet as GlucoBoost, Fermented Nutrition, Luxemburg, WI, replacing soybean meal; n = 19). Liver biopsies were performed at 14 and 28 DIM for analysis of mRNA expression by quantitative real-time PCR and lvTG per unit of liver DNA. Blood samples were collected at 3, 7, 14, and 28 DIM for metabolite analysis. Models were fitted using the GLIMMIX procedure of SAS (SAS 9.4); linear predictors included the fixed effects of treatment, DRTC, and interaction, and the random effects of block and cow(treatment). Cows supplemented with FACW had increased (P < 0.05) mRNA expression of G6PC at 14, and PC at 14 and 28 DIM, relative to CTL. Supplementation with FACW did not alter (P > 0.31) mRNA expression of the PCK1, resulting in a 1.9-fold greater (P = 0.04) PC:PCK1 for FACW cows compared with CTL. There was no evidence (P > 0.26) that FACW altered LDHA or LDHB, although post-transcriptional regulation was not examined. There was no evidence (P > 0.26) for altered expression of inflammatory genes. There was marginal evidence (P = 0.09) for a 34.8% lower lvTG at 14 DIM, and 10% lower (P = 0.05) plasma urea nitrogen with FACW supplementation compared with CTL. There was no evidence (P > 0.21) for differences between treatments on serum haptoglobin and plasma alanine aminotransferase, aspartate aminotransferase, or albumin. Increased G6PC, together with previously reported increased blood glucose and similar milk lactose output, suggests that FACW provided gluconeogenic precursors. Increased hepatic PC:PCK1, together with previously reported decreased plasma β-hydroxybutyrate and the marginal evidence for lower lvTG, suggests greater complete hepatic oxidative capacity of fatty acids in FACW cows.