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 ± 13.9kg) 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 1 of 2 treatments. The treatments were 1) Control, basal finishing diet only (CON); 2) SCFP, 1-d feeding of liquid SCFP (infused into the rumen via the cannula at 11mL/100kg BW) followed by daily feeding of dry SCFP (12g/d, top-dressed). Feed and spot fecal samples were collected during days 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 day 21 before the morning feeding. Rumen fluid samples were collected on days 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 dry matter intake (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 day 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 day 5 (P = 0.08) and significantly increased total VFA on day 21 (P = 0.05). Ruminal NH3-N was reduced (P = 0.02) on day 21 by supplementing SCFP. Treatment did not affect the production of proinflammatory cytokines, interleukin (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 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.