At the onset of lactation, inflammation and stress of the endoplasmic reticulum (ER) occurs in the liver resulting in impaired hepatic function with undesirable effects on the health status of high yielding dairy cows. The present study investigated the hypothesis that feeding a polyphenol-rich grape seed and grape marc extract (GSGME) has the potential to suppress the inflammatory process and ER stress in the liver during early lactation. Twenty-eight German Holstein cows received either a total mixed ration (TMR, control group) or the same TMR supplemented with 1% GSGME (polyphenol content: 43 mg/g; AntaOx, Dr. Eckel GmbH) from wk 3 ap to wk 9 pp (experimental unit: single cow). Milk, blood, and liver samples were taken. Data were statistically evaluated by the linear mixed-effects model of R. Dry matter intake of the cows did not differ between the 2 groups. However, the GSGME group had a greater milk performance (Δ milk yield: + 3.7 kg/d; P < 0.05; Δ energy corrected milk: + 2.9 kg, P < 0.05) from wk 2 to 9 of lactation. Cows of the GSGME group had lower hepatic mRNA concentrations of FGF21, a key marker of ER stress (P < 0.05) and a tendency toward lower hepatic levels of triglycerides and cholesterol (P < 0.15). A reduction of mRNA concentrations of various other ER stress response-related and pro-inflammatory genes could be observed in the GSGME group. Feeding GSGME had no effect on the antioxidative status (α-tocopherol, β-carotene, TBARS and total antioxidant capacity in plasma). In conclusion, the study suggests that feeding polyphenol-rich plant extracts during early lactation could be a useful strategy to prevent inflammatory processes and ER stress in the liver and thus improve milk yield and animal health in dairy cows.