Mitigation of exercise-induced stress is of key interest in determining ways to optimize performance horse health. To test the hypothesis that dietary supplementation of a Saccharomyces cerevisiae fermentation product would decrease markers of exercise-induced stress and inflammation in young horses, Quarter Horse yearlings (mean ± SD; 9 ± 1 mo) were randomly assigned to receive either no supplementation (CON; n = 8) or 21 g/d Saccharomyces cerevisiae fermentation product (10.5 g/feeding twice daily; SCFP; n = 10) top dressed on a basal diet of custom-formulated grain, as well as ad libitum Coastal bermudagrass hay. After 8 wk of dietary treatments, horses underwent a 2-h submaximal exercise test (SET) on a free-stall mechanical exerciser. Serum was collected before dietary treatment supplementation (wk 0), and at wk 8 pre-SET, and 0, 1, and 6 h post-SET, and analyzed for concentrations of cortisol and serum amyloid A (SAA) by commercial ELISA, and for cytokine concentrations by commercial bead-based ELISA. Data were analyzed using linear models with repeated measures in SAS v9.4. From wk 0 to 8 (pre-SET), serum cortisol decreased (P = 0.01) and SAA did not change but neither were affected by diet. Serum concentrations of all cytokines decreased from wk 0 to 8 (P ≤ 0.008), but granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-8 (IL-8) decreased to a greater extent in CON than in SCFP horses (P ≤ 0.003). In response to the wk 8 SET, serum cortisol increased in all horses (P < 0.0001), but returned to pre-SET levels by 1 h post-SET in horses receiving SCFP. At 6 h post-SET, cortisol concentrations in CON horses returned to pre-SET concentrations, while cortisol declined further in SCFP horses to below pre-SET levels (P = 0.0002) and lower than CON (P = 0.003) at that time point. Serum amyloid A increased at 6 h post-SET in CON (P < 0.0001) but was unchanged through 6 h in SCFP horses. All cytokines except G-CSF increased in response to the SET (P < 0.0001), but showed differing response patterns. Concentrations of IL-1β, IL-6, and tumor necrosis factor alpha (TNFα) were lesser (P ≤ 0.05), and concentrations of G-CSF and IL-18 tended to be lesser (P ≤ 0.09) in SCFP compared to CON horses throughout recovery from the SET. In summary, 8 wk of dietary supplementation with 21 g/d of SCFP may mitigate cellular stress following a single, prolonged submaximal exercise bout in young horses.