Abstract The purpose of this study was to investigate the effects of Saccharomyces yeast postbiotics (celluTEIN, Puretein Biosecience LLC, Minneapolis, MN, USA) on the intestinal health and growth performance of newly weaned pigs challenged with F18+ Escherichia coli. Nursery pigs [n =36; initial body weight (BW) = 6.42 ± 0.33 kg BW] were allotted into three dietary treatments utilizing a randomized complete block design with sex and initial BW as blocks. The dietary treatments included a negative control (NC: basal diet, no challenge), a positive control (PC: basal diet, challenged with F18+ E. coli), and SYP (basal diet with Saccharomyces yeast postbiotics at 175 g/ton of feed, challenged with F18+ E. coli). Basal diets were formulated to meet NRC (2012) requirements with Saccharomyces yeast postbiotics replacing corn in the basal diet. Pigs were fed for 28 d in 3 phases (P1: 11 d, P2: 10 d, P3: 7 d). Pigs in PC and Saccharomyces yeast postbiotics were orally inoculated with F18+ E. coli (2.0 × 1010 CFU), whereas the NC group received sterile saline, given in 4 doses beginning on d 7 after weaning. Throughout, fecal score, BW, and feed intake were recorded to calculate average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G:F). At d 28, all pigs were euthanized for sampling of the jejunal mucosa to analyze oxidative stress and immune status, as well as microbiota diversity and relative abundance. Data were analyzed using the Proc Mixed in SAS 9.4 (Cary, NC). Overall, PC reduced (P < 0.05) the BW, ADG, and ADFI of pigs. The SYP had a tendency (P = 0.098) to improve the ADFI of pigs challenged with F18+ E. coli. The fecal score of pigs fed SYP were improved (P < 0.05) on d 7 to 18 of the post-challenge period when compared with PC. Furthermore, SYP reduced protein carbonyl (P < 0.05), reduced (P < 0.05) the relative abundance of Erysipelotrichaceae, and had a tendency to increase Leuconostocaceae (P = 0.090), Streptococcaceae (P = 0.068), Corynebacteriaceae (P = 0.085), and had a tendency to reduce (P = 0.077) Ruminococcaceae when compared with PC. Additionally, SYP reduced (P < 0.05) gene expression of toll-like receptor 4 (TLR4) and increased (P < 0.05) gene expression mammalian target of rapamycin (mTOR), when compared with PC. In conclusion, challenge with F18+ E. coli increased fecal score, disrupted the microbiota composition in the jejunal mucosa, and increased gene expression associated with recognition of pathogens, without any impact on inflammation; therefore, negatively affecting growth performance. Saccharomyces yeast postbiotics could reduce the negative effects associated with F18+ E. coli infection by altering microbial diversity and reducing inflammation associated with expression of TLR4, and oxidative stress products, without changes in growth.