Objectives were to determine the effects of supplementing a blend of probiotics, β-glucan, mannanoligosaccharides, and small-molecular-weight molecules from colostrum on the performance and health of high-risk Holstein calves. One hundred bull calves were acquired from a local calf ranch within 24 h of birth and randomly assigned to 1 of 5 treatments added to the milk replacer: Control (CON), no additive; Immu-Prime (ImmPr), 1.5 g/d ImmPr first 3 d only; (3) Beta glucan (BG), 1 g/d BG; (4) Mannanoligosaccharide + Bacillus subtilis (MOS+Bs), 3 g/d MOS + 4 × 10⁹ cfu/d Bacillus subtilis; and PROVIDA (PRO), blend of 2 × 10⁹Lactobacillus casei and Enterococcus faecium + 2 × 10⁹Saccharomyces cerevisae. Calves were weaned at d 56, comingled, and treatment carry-over effects were evaluated through d 84. Starter intake was measured daily and BW weekly. Peripheral blood samples were collected on d 1, 3, 7, 14, 21, 42, 56, and 84 and analyzed for hematology and serum analyzed for haptoglobin concentrations. Neutrophil function was assessed through surface L-selectin and phagocytic and oxidative burst activities. Data were analyzed using Proc Mixed. The BG consumed the most starter from d 1 to 28 and both the MOS+Bs and ImmPr consumed more than the CON (P = 0.016). Preweaned ADG was greater for PRO and BG when compared with the CON (P = 0.038), both the MOS+Bs and ImmPr were not different than the other treatments. There was no carry-over effect on ADG (P = 0.879). There was a tendency for BG, MOS+Bs, and PRO to have reduced serum haptoglobin throughout the study (P = 0.075). Total leukocyte, neutrophil, and lymphocyte counts were reduced among MOS+Bs calves (P ≤ 0.003), whereas BG calves tended to have the greatest neutrophil:lymphocyte ratio (0.051). Neutrophil L-selectin was reduced among BG (P = 0.030), whereas PRO was not different than BG or the other treatments. Neutrophil oxidative burst was reduced among BG and PRO when compared with CON and ImmPr (P = 0.011), but MOS+Bs was not different than any treatment. Supplementing BG, MOS+Bs, and PRO all influenced performance and health of high risk calves, but the mechanisms appear to be different.