This study was designed to investigate the effects of supplementing SmartCare (SC; Diamond V, Cedar Rapids, IA) in milk replacer and Original XPC (XPC; Diamond V) in calf starter on performance and health of preweaned calves following an oral challenge with Salmonella enterica. The study was performed in two 35-d periods with 30 Holstein bull calves (2 ± 1 d of age) per period. In each period, calves were blocked by location in the barn and randomly assigned to treatments that included control, base milk replacer and calf starter with no added Saccharomyces cerevisiae fermentation products; SC, milk replacer with 1 g of SC/calf per day and base calf starter; and SC+XPC, milk replacer with 1 g of SC/calf per day and calf starter with 0.5% XPC on a dry matter basis. Calves were fed 350 g of milk replacer solids at 14% dry matter twice daily at 0700 and 1700 h. Calf starter and water were offered ad libitum and intakes were recorded daily. Calves were challenged with 108 cfu of sulfamethazine-resistant Salmonella enterica serotype Typhimurium orally on d 14 of the study. Fecal Salmonella shedding was determined on d 14 to 21 (daily), 24, 28, and 35 using selective media. Blood samples were collected on d 0, 7, 14, 16, 18, 21, 24, 28, and 35 and analyzed for hematology; plasma were analyzed for haptoglobin concentrations. All data were reported as CON, SC, and SC+XPC, respectively. Calf starter intake was increased from d 22 to 35 among SC+XPC calves and from d 29 to 35 among SC calves. The SC+XPC calves had a lower neutrophil-to-lymphocyte ratio (0.81, 0.83, and 0.69 ± 0.051) throughout the study. The SC+XPC calves also had lower hematocrits (35.1, 35.3, and 33.4 ± 0.54%) and hemoglobin concentrations (10.8, 10.6, and 10.1 ± 0.16 mg/dL) throughout the study. We found a tendency for calves fed SC and SC+XPC to have more solid fecal scores during the week after the challenge. We observed no treatment or treatment × time differences on plasma haptoglobin concentrations (63, 48, and 60 ± 0.5 µg/mL). No treatment differences were observed in the fecal shedding of the Salmonella; however, we noted a tendency for a treatment difference in the percentage of calves positive for Salmonella present in the ileal tissue at d 21 after the challenge (25, 50, and 60%). Supplementing preweaned Holstein calves with both SC in milk replacer and XPC in calf starter improved starter intake and improved fecal consistency immediately after a mild Salmonella enterica challenge, but more data are needed to further understand how these yeast fermentation products influence the immune responses to Salmonella enterica.