This study evaluated the efficacy of epidermal growth factor (EGF) in piglets challenged with enterotoxigenic Escherichia coli K88 (ETEC). A total of 28 piglets were assigned to the following dietary treatments for 14 d: negative control (NC) (basal diet containing supernatant without EGF), PC (NC + 2.5 g antibiotic·kg⁻¹ feed), EGF120 [basal diet + supernatant with 120 μg EGF·kg⁻¹ body weight (BW)·d⁻¹], and EGF180 (basal diet + supernatant with 180 μg EGF·kg⁻¹ BW·d⁻¹). After a 6 d acclimation period, each pig was gavaged with 6 mL (2.4 × 10¹³ cfu·mL⁻¹) of ETEC on the morning of day 7. Overall, piglets fed the EGF and PC diets tended to have higher gain to feed ratio than those fed the NC diet (P = 0.063). Pigs fed EGF diets had lower rectal temperature than those fed the NC diet at 6 h after challenge (P < 0.05). Serum and ileal malondialdehyde concentrations were higher in piglets fed the NC diet compared with those fed EGF and PC diets on days 6 and 7 after challenge, respectively (P < 0.05). In conclusion, EGF has the potential to reduce oxidative stress and body temperature elevation in piglets exposed to ETEC while supporting better feed efficiency.