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Growth performance and physiological responses of nursery piglets when fed enzymatically treated yeast (HY40) and pharmacological ZnO alone or in combination were investigated. A total of 144 pigs (21 d old, BW 7.32 ± 0.55 kg) were placed in 36 pens (4 pigs/pen). Pigs were randomly assigned to one of four dietary treatments (n = 9): 1) control corn-wheat-soybean meal diet (control), 2) control + HY40 (HY40), 3) control + (ZnO) and 4) control + HY40 + ZnO (HY40+ZnO). Inclusion of HY40 and ZnO was 0.5% and 3,000 ppm in phase I (days 0 to 14), respectively, and halved in phase II (days 15 to 42). All diets contained 0.2% TiO2 for determination of apparent total tract digestibility (ATTD) of components. Body weight and feed disappearance were recorded weekly. One pig per pen was killed for organ weights, blood, and tissue samples on day 14. Except for phase II, when HY40 + ZnO pigs had greater average daily feed intake (P = 0.004) than all other treatments, there were no (P0.05) interactions between HY40 and ZnO on growth performance. Pigs fed HY40 or ZnO containing diets were heavier (P0.05) than pigs fed without by the end of the study. On day 14, pigs fed additives exhibited higher (P ≤ 0.009) ATTD of dry matter (DM) and gross energy (GE) than control pigs. On day 28, pigs fed control, HY40, and HY40 + ZnO had greater (P ≤ 0.022) ATTD of DM, crude protein, and GE than piglets fed ZnO only. Pigs fed HY40 + ZnO had lower ileal digesta Escherichia coli concentration (P0.05) than HY40 and control pigs. Ileal digesta of pigs fed ZnO diets had higher lactobacillus to E. coli ratio (1.44 vs. 1.20; P = 0.001), exhibited higher concentrations of acetic (P = 0.01) and butyric acid (P = 0.01) but lower lactic (P = 0.02) and total short chain fatty acids (P = 0.033) than pigs fed non-ZnO diets. Greater (P0.05) mRNA expression of nutrient transporters, tight junction proteins, and fecal excretion of zinc (Zn) was observed in ZnO pigs relative to non-ZnO pigs. Pigs fed HY40 diets had greater (P = 0.002) villus height to crypt depth ratio (VH:CD) than non-HY40 pigs. The concentration of plasma IgA was higher (P = 0.04) in HY40 + ZnO pigs relative to other pigs, whereas HY40 pigs showed higher (P0.001) jejunal IgA than non-HY40 pigs. Although the mode of action of HY40 and ZnO differed, the present study indicated that HY40 improved growth performance and jejunal function and immunity, making HY40 an effective alternative to pharmacological ZnO in nursery pigs feeding programs.Abrupt weaning of pig results in nutritional, environmental, and psychological stresses leading to reduced feed intake, little or no weight gain and in some instances diarrhea, morbidity, and mortality. The post-weaning growth performance lag is often managed by use of antimicrobial growth promoters (AGP), pharmacological levels of trace elements such as zinc oxide (ZnO), specialty feed ingredients, and additives. However, many jurisdictions have already banned, and others are considering banning/restricting use of AGP to abate burgeoning levels of antimicrobial resistance in pathogens of animal and human. The European Union confirmed banning pharmacological ZnO effective June 2022 because of environmental pollution. In this context, identifying alternative nutritional strategies for managing newly weaned pigs is of global concern. Yeast derivatives have been proposed to be beneficial in transitioning piglets. However, there is little available information on comparative efficacy of yeast derivatives and pharmacological ZnO. The current study demonstrated that enzymatically treated yeast (HY40) had positive effects on growth, intestinal histomorphology, nutrient digestibility, and immune indices in nursery pigs. Through differing modes of action, overall growth performance of HY40 piglets was comparable to that of pharmacological ZnO piglets.