Study objectives were to evaluate the effects of supplementing a Saccharomyces cerevisiae fermentation product (SCFP) on metabolism, the acute phase protein response (APPR), and production parameters during heat stress (HS). Twenty multiparous, lactating Holstein cows were randomly assigned to 1 of 2 dietary treatments: 1) a control diet (CON; n = 10) or 2) a control diet supplemented with 19 g/d of SCFP (n = 10; NutriTek; Diamond V, Cedar Rapids, IA). Cows were fed their respective diets for 21 d before study initiation. The trial consisted of 2 experimental periods (P). During P1 (4 d), cows were fed ad libitum and housed in thermoneutral conditions (TN). During P2 (7 d), HS was induced by using an electric heat blanket (EHB; Thermotex Therapy Systems Ltd. Calgary, AB, Canada). Cows were fitted with the EHB for the entirety of P2. Rectal temperature (Tr), respiration rate (RR), and skin temperature (Ts) were obtained twice daily (0600 and 1800 h) during both TN and HS. Overall, the HS increased Tr, RR, and Ts (1.4°C, 54 breaths/min and 4.8°C, respectively; P < 0.01) relative to TN but there were no dietary treatment differences detected. Compared with TN, HS decreased DMI and milk yield (36 and 26%, respectively; P < 0.01), and the decrease was similar between dietary treatments. During HS, milk fat and MUN increased (17 and 30%; respectively; P < 0.01) and milk protein and lactose decreased (7 and 1.7%; respectively; P < 0.01). Milk SCC was not affected by HS but was decreased (19%; P = 0.07) in SCFP-fed cows. During HS, circulating cortisol increased (48%; P = 0.04) in CON-fed cows, but did not change in SCFP-fed cows. During HS, circulating lipopolysaccharide binding protein and serum amyloid A (SAA) increased (2-and 4-fold, respectively P < 0.01) and SAA decreased on d 5 of HS in SCFP-fed cows (33%; P = 0.07) relative to CON. During HS, circulating white blood cells and neutrophils increased (9 and 26%; respectively; P ≤ 0.05) in SCFP-fed cows compared with CON cows. In conclusion, HS caused an APPR and feeding SCFP blunted the cortisol and SAA response and mediated leukocyte dynamics during HS.