The objective of this study was to determine the effects of Protemace on the performance and health of Jersey calves challenged with Salmonella enterica serotype Typhimurium. Jersey bull calves within 1 d of birth were blocked by total serum protein and initial BW and randomly assigned to treatments in a 2 × 2 factorial arrangement with Protemace (PM) and Salmonella enterica (ST) as the main effects (n = 8). Calves challenged with ST were administered 5.5 × 10⁶ cfu in the AM milk replacer on d 7. Calves supplemented with PM had 8 mL added directly to the bottle before each feeding. All calves were fed 300 g of a 22% CP and 20% fat milk replacer twice daily. Calves had ad libitum access to a starter. Blood samples and body weight measurements were taken at d 0, 7, 10, 14, and 21. All calves were harvested on d 21, and duodenum and ileum samples collected for histomorphological measurements. Data were analyzed as a repeated measures with the fixed effects of PM, ST, time, and all possible interactions; block was included as an additional random effect. There was no treatment × time difference on ADG (P = 0.802); however, ST calves tended to decrease ADG (P = 0.054). No treatment × time difference was observed in rectal temperature (P = 0.883), but ST calves had greater rectal temperature than unchallenged calves at d 9 to 12 post challenge (P < 0.001). There was no treatment × time or treatment differences in fecal dry matter percentage either before or post challenge (P ≥0.261). There was no treatment × time difference in plasma haptoglobin concentration (P = 0.736); however, calves supplemented with PM had decreased concentrations (P = 0.016). The ST calves had a tendency (P = 0.082) for reduced villi:crypt in the duodenum, but PM calves had greater villi:crypt in the duodenum (P = 0.040). Additionally, the ST calves had a tendency (P = 0.072) for reduced villi:crypt in the ileum; however, there was no effect due to PM (P = 0.154). These data indicate that Protemace reduced some inflammation indices of Jersey calves challenged with Salmonella enterica on d 7 of life.