This study evaluated the effects of supplementing dairy calves with Saccharomyces cerevisiae fermentation-derived postbiotics (SCFP) on growth, metabolism, immune status, and first lactation performance. Eighteen Holstein heifer calves were blocked by birth body weight and serum total protein and randomly assigned to control (CTR; n = 9; no supplementation) or SCFP (n = 9; 1 g/d SmartCare^® in milk replacer until weaning plus 5 g/d NutriTek^® until 70 d; Diamond V™, USA). Calves were weaned at 60 d and monitored until 160 d. Feed intake did not differ between groups. SCFP calves had greater post-weaning average daily gain from 71 to 100 d (0.93 vs. 0.60 kg/d, SCFP and CTR, respectively) and body weight from 100 to 160 d. They tended to have greater plasma β-hydroxybutyrate at 60 (0.32 vs. 0.27 mmol/L, SCFP and CTR, respectively) and 70 d (0.46 vs. 0.42, SCFP and CTR, respectively) and urea at 70 d (4.89 vs. 4.33 mmol/L, SCFP and CTR, respectively) and had greater acetate (515 vs. 384 μmol/L, SCFP and CTR, respectively) and propionate (33.13 vs. 22.4 ± 4.86 μmol/L, SCFP and CTR, respectively) at 60 d. SCFP calves also had lower nonesterified fatty acids at 21 d (0.23 vs. 0.38 mmol/L, SCFP and CTR, respectively), suggesting reduced energy mobilization during the most critical pre-weaning stage. Plasma myeloperoxidase was greater at 70 d (340 vs. 262 U/L, SCFP and CTR, respectively), as was phagocytosis by polymorphonuclear neutrophils at 60 (+10.4%) and 70 d (+8.2%). Feeding SCFP increased rumen activity and plasma volatile fatty acid concentrations, likely due to enhanced nutrient absorption and reduced weaning stress. SCFP calves exhibited a better immune response to lipopolysaccharide stimulation, as indicated by leukocyte gene expression, MPO, and PMN phagocytosis. Metagenomic analyses showed minor but significant changes in early-life microbiota composition at 7, 21, and 42 d. During first lactation, SCFP cows produced 2.1 kg/d more milk in the first 100 days in milk compared with CTR. In conclusion, early supplementation with SCFP supported rumen development, improved metabolic and immune function, and may enhance future productivity in dairy cows.