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Epidermal growth factor (EGF) is a cytoprotective peptide that plays a crucial role in gut growth and health. The study mainly explored the effects of EGF on the intestinal antioxidant capacity, inflammatory response, immune status in weaning piglets. Forty-two 21-day-old weaned piglets were randomly assigned to three treatments consisting of a same basic diet containing 0 (control), 200, or 400 µg/kg EGF, respectively. There were 14 replicates per treatment, and 7 piglets per treatment were sampled on days 7 and 14 of the experiment. Dietary supplementation of 200 µg/kg EGF increased the activity of superoxide dismutase (SOD) during the entire experimental period. This supplementation decreased malondialdehyde (MDA) content whereas it increased serum immunoglobulin A (IgA) content on day 7 post-weaning. Animals receiving the diet supplemented with 400 µg/kg EGF decreased concentration of tumor necrosis factor-α (TNF-α) and tended to increase the level of secretory immunoglobulin A (SIgA) in the overall experimental period. In addition, the phosphorylation level of nuclear factor-κB (NF-κB) p65 was higher for piglets fed EGF diet. In summary, EGF can enhance intestinal antioxidant capacity, decrease inflammatory response, and increase immune status in weaned piglets, suggesting that EGF has a positive role in piglet gut health.