The study aimed to determine the effects of a postbiotic feeding program consisting of liquid and dry Saccharomyces cerevisiae fermentation product (SCFP) on ruminal fermentation, digestibility, and plasma metabolome of Holstein steers receiving a grain-based diet. Eight Holstein steers (Body weight; BW 467 ± 13.9 kg) equipped with rumen cannulas were used in a crossover design study, with 21 d per period and a 7 d washout period in between periods. Steers were stratified by initial BW and assigned to one of two treatments. The treatments were (1) Control, basal finishing diet only (CON); (2) SCFP, one-day feeding of liquid SCFP (infused into the rumen via the cannula at 11 mL/100 kg BW) followed by daily feeding of dry SCFP (12 g/d, top-dressed). Feed and spot fecal samples were collected during d 17 to 20 for determination of digestibility and fecal excretion of N, P, Cu, and Zn. Digestibility was measured using acid-insoluble ash as an internal marker. Blood samples were collected on d 21 before the morning feeding. Rumen fluid samples were collected on d 0, 1, 2, 3, 5 and 21 via rumen cannula. Results were analyzed with the GLIMMIX procedure of SAS 9.4 (SAS, 2023). Treatment did not affect DMI (P = 0.15) and digestibility (P ≥ 0.62). The fecal output and absorption of Zn, Cu, P, and N were not affected (P > 0.22) by treatment. On d 1, the liquid SCFP supplementation tended to reduce (P = 0.07) ruminal VFA concentration and increased (P < 0.01) the molar proportion of valerate. Feeding SCFP tended to increase total ruminal VFA on d 5 (P = 0.08) and significantly increased total VFA on d 21 (P = 0.05). Ruminal NH3-N was reduced (P = 0.02) on d 21 by supplementing SCFP. Treatment did not affect the production of proinflammatory cytokines, IL-1β (P > 0.19) and IL-6 (P > 0.12) in the whole blood in response to various toll-like receptor stimulants in vitro. Feeding SCFP enriched (P ≤ 0.05) plasma metabolic pathways, including citric acid cycle, pyrimidine metabolism, glycolysis/gluconeogenesis, retinol metabolism, and inositol phosphate metabolism pathways. In summary, supplementing liquid SCFP with subsequent dry SCFP enhanced ruminal total VFA production and reduced NH3-N concentration nitrogen in the rumen. Furthermore, feeding SCFP enriched several important pathways in lipid, protein, and glucose metabolism, which may improve feed efficiency of energy and protein in Holstein steers.