Nuclear factor erythroid 2 like 2 (NFE2L2) is a transcription factor that regulates the expression of antioxidant proteins. We investigated the effect of increasing Met supply during the periparturient period on NFE2L2, its targets and the potential for epigenetics in its regulation. Multiparous cows were assigned to a control diet or the control plus rumen-protected methionine (MET; Mepron, Evonik Nutrition & Care GmbH) to ensure a ratio of Lys to Met in the metabolizable protein close to 2.8:1. Mepron (0.09–0.10% of the dry matter intake) was fed from −28 to 30 d relative to parturition. Liver was sampled from 8 cows/treatment at −10, +10, and +30 d relative to parturition. NFE2L2 and DNA methyltransferases (DNMT) were analyzed by protein blotting, while NFE2L2 targets and NFE2L2 DNA methylation were analyzed by RT-PCR. Glutathione, global DNA methylation, and histone H3 lysine 4 tri-methylation (H3K4me3) were analyzed by colorimetric commercial kits. Data were analyzed using a Mixed model considering block as random effect and treatment, time and its interaction as fixed effect. Compared with control, MET-fed cows had greater (P = 0.04) protein expression of phosphorylated NFE2L2 and tended to have greater (P = 0.07) total NFE2L2. These results agree with the lower (P = 0.03) DNA methylation of the NFE2L2 promoter, which indicates a higher rate of NFE2L2 transcription. Among the 7 NFE2L2 target genes analyzed, TXNRD1, HMOX1, PIR, and NQO1 were upregulated (P ≤ 0.05) by MET supply. Expression of TNX, FECH, and FTH1 was not affected (P ≥ 0.10) by MET. Hepatic glutathione was greater (P = 0.01) and global DNA methylation lower (P = 0.04) in MET-supplemented cows. The protein expression of the de novo DNMT3A and the maintenance DNMT1 were not affected (P ≥ 0.10) by MET-supply; however, DNMT3A protein expression increased (P = 0.05) over time. A treatment × time interaction (P = 0.05) was observed for the protein expression of the de novo DNMT3B because of an increase over time. Increasing MET-supply in the diet enhanced (P = 0.04) the concentration of H3K4me3 especially in the postpartum period. Together, these data demonstrate that MET supply during the periparturient period might prevent liver damage by inflammation and oxidative stress through its effect on the NFE2L2 pathway, which is at least in part regulated epigenetically.