The peripartal period is characterized by marked changes in inflammatory status that are functionally related with impaired immune and metabolic responses in the cow. We examined blood metabolites and expression of genes related to inflammation and ER stress in cows assigned (6/diet) to a control (high-straw, CON; NEL = 1.34 Mcal/kg) or moderate-energy (OVE; NEL = 1.62 Mcal/kg) diet during the entire dry period. All cows were fed a common lactation diet (NEL = 1.69 Mcal/ kg) postpartum. Blood was collected on d (±3) −14, −5, −2, −1, 0, 1, 2, 5, 7, 10, 14 and 21 d relative to parturition. A percutaneous liver tissue biopsy was harvested at −14, 7, 14, and 30 d relative to parturition for transcript profiling via quantitative PCR. Estimated prepartal energy balance (EBAL) OVE was greater (P < 0.05) and averaged 159% of requirements compared with 102% in CON. However, EBAL during the first week postpartum was lower in OVE (83% vs. 89% of requirements). After parturition the concentration of ceruloplasmin, creatinine, bilirubin and reactive oxygen metabolites (ROM) was greater (Diet × Time; P < 0.05) in OVE. Around calving the expression of ER and oxidative stress indicator genes XBP1, PERK, GRP94 and HSP40 was lower in OVE than CON but TRB3, HSPA1A, HSPA1B and CREB3L3 had greater (Diet × Time; P < 0.05) expression in OVE. Expression postpartum of the inflammatory genes NFKB1, RELA, CHUK, MYD88, TNF, SAA3, and PTX3 increased (Diet × Time; P < 0.05) in OVE. Genes associated with cell growth (mTOR, RPTOR, AKT3, TP53) also had greater (Diet × Time; P < 0.05) expression in OVE after parturition. Overall, results indicated that negative EBAL induced by prepartal OVE was associated with hepatic pro-inflammatory and pro-stress upregulation.