A total of 28 piglets weaned at 21 d of age (6.94 ± 0.28 kg of body weight) were assigned to one of four dietary treatments for 14 d: (1) negative control (NC; a corn–wheat–soybean meal diet), (2) positive control [PC; NC + 0.025% antimicrobial growth promoter (AGP)], (3) ROD2 [2% red-osier dogwood (ROD)], and (4) ROD4 (4% ROD). All pigs were orally inoculated with Escherichia coli K88⁺ on day 8. The pre-planned orthogonal test was performed to compare (1) NC vs. PC and (2) NC vs. ROD. The inclusion of ROD in a nursery diet increased (P < 0.05) superoxide dismutase (SOD) activities and decreased (P < 0.05) malondialdehyde (MDA) concentrations in the serum. Moreover, pigs fed with ROD diets had shallower (P < 0.05) crypt depth and higher (P < 0.05) villus height to crypt depth ratio than those fed the NC diet. Dietary AGP supplementation reduced (P < 0.05) the MDA concentration in the ileum and serum at 24 h after challenge, and improved (P < 0.01) the SOD activities in the serum. In conclusion, the inclusion of ROD in a nursery diet enhanced the antioxidative defense system and intestinal morphology, showing comparable effects with AGP supplementation.