Reducing stress is an important goal in poultry production. The Saccharomyces cerevisiae-derived yeast fermentation product Original XPC (XPC, Diamond V Mills, Cedar Rapids, IA, United States) has been shown to reduce the severity of enteric infection and reduce measures of stress in poultry exposed to acute or chronic stress. However, the effect of dietary supplementation of yeast fermentate on other physiological parameters and its mode of action in reducing stress remains unclear. This work aimed to investigate the effects of supplementing XPC or its liquid equivalent, AviCare (Diamond V Mills), on measures of stress susceptibility, health and well-being in poultry exposed to acute and chronic stressors. Three consecutive experiments were conducted to evaluate the effects of yeast fermentate supplementation on measures of stress, growth and feed efficiency in Cobb 500 male broilers exposed to acute and rearing stressors. Both XPC and AviCare consistently and equally reduced measures of short- and long-term stress across all 3 experiments, although trends in body weight gain and feed efficiency were inconsistent. A fourth experiment investigated the effects of XPC and AviCare on measures of stress, plasma biochemistry, cecal microbiome and expression of stress- and immune-related genes in Cobb 500 male broilers. Both XPC and AviCare reduced stress by reducing expression of the ACTH receptor, and modulated immune activity by reducing IL10 and CYP1A2 gene expression as well as plasma IL-1?. However, cecal microbiome and antioxidative capacity were not affected after 42 d. Finally, 2 consecutive experiments were conducted to evaluate the effect of XPC and AviCare on measures of intestinal health in Cobb 500 male broilers and mixed-sex Pekin ducks exposed to cyclic heat stress during the last 14 d of growth. In both experiments yeast fermentate attenuated the negative effects of heat stress on villus length and villus/crypt ratio but not goblet cell density. Yeast fermentate also affected metabolism but did not improve electrolyte balance. In conclusion, adding yeast fermentate to the feed or drinking water reduced stress susceptibility by reducing glucocorticoid production, supported intestinal cell survival during cyclic heat stress, and modulated inflammatory processes in poultry exposed to rearing stress but not cyclic heat stress.