The objective of this study was to evaluate the efficacy of supplemental rumen-protected methionine (MET) and choline (CHO) on alleviating inflammation and oxidative stress through their use for synthesis of antioxidants or other methyl-group requiring compounds. Forty-eight multiparous Holstein cows were used in a randomized complete block design with 2 × 2 factorial arrangement of MET (Smartamine M, Adisseo NA) and CHO (ReaShure, Balchem Inc.) level (with or without). Treatments (12 cows each) were control (CON), no MET or CHO; CON+MET (SMA); CON+CHO (REA); and CON+MET+CHO (MIX). From −50 d to −21 d before expected calving, all cows received the same diet (1.24 Mcal/kg DM) with no MET or CHO. From −21 d to calving, cows received the same close-up diet (1.54 Mcal/kg DM) and were assigned randomly to each treatment. From calving to 30 d, cows were on the same postpartal diet (1.69 Mcal/kg DM) and continued to receive the same treatments until 30 d. MET supplementation was adjusted daily at 0.08% DM of diet and CHO was supplemented at 60 g/cow/d. Blood was collected at −10, 4, 8, 20, and 30 d for profiling of 16 biomarkers. Neutrophil and monocyte phagocytosis and oxidative burst were assessed at d 1, 3, 7, 14, and 28 d. MET (SMA, MIX) led to greater (P = 0.04; 36.55 vs. 35.53 g/L, SEM 0.35) albumin, lower (P = 0.08; 0.35 vs. 0.47 g/L, SEM 0.05) haptoglobin, and greater (P = 0.07, 93.09 vs. 84.54 U/ml, SEM 3.20) paraoxonase (antioxidant) compared with other treatments. This suggests a more pronounced inflammatory state in cows without supplemental MET. MET-supplemented cows had greater (P < 0.01; 60.43 vs. 54.88%, SEM 1.65) neutrophil phagocytosis capacity. Both SMA and REA had greater (P < 0.01) monocyte (SMA, 26.93 vs. 16.96%, SEM 2.71; REA, 25.96 vs. 16.96%, SEM 2.52) and neutrophil (SMA, 59.19 vs. 43.32%, SEM 4.58; REA, 53.89 vs. 43.32%, SEM 4.25) oxidative burst activity compared with CON. Data suggest that supplementing rumen-protected methionine peripartal has positive effects on immune and liver function at least in part by reducing oxidative stress and inflammation.