A 2 × 2 factorial experiment was conducted to determine the effects of rearing environment (indoor (In) v. outdoor (Out)) and dietary zinc oxide (ZnO) supplementation (0 (−Zn) v. 3100 (+Zn) mg/kg feed) on the response of weaned pigs to a challenge infection with enterotoxigenic Escherichia coli (ETEC). Pigs from the two rearing environments were weaned onto trial diets at 4 weeks of age, moved into conventional accommodation and infected 3 days later with 109 CFU ETEC per os. Faecal ETEC shedding was determined before and after challenge. After 7 days of ETEC infection, all pigs were euthanized for gut lactic acid bacteria (LAB)-to-coliform ratio, pH and small intestine morphological measurements. Both ZnO and outdoor rearing reduced ETEC excretion, and these effects were additive. Outdoor rearing increased small intestine and colon tissue weight. ZnO increased villus height and goblet cell number in the upper small intestine, LAB-to-coliform ratio (through reduced coliforms) in the lower small intestine and proximal colon, and improved growth performance. There were interactive effects of rearing environment and ZnO supplementation on upper small intestine villus height and daily gain, as outdoor rearing conferred advantages on these variables only with ZnO dietary supplementation. Daily gains were 233, 174, 277 and 347 (s.e.m. 27.2) g/day for the In − Zn, Out − Zn, In + Zn and Out + Zn, respectively. These results suggest different, but complementary mechanisms of intestinal health and performance in outdoor-reared pigs and those offered ZnO supplemented diets. The results indicate that the benefits of ZnO to the weaned pig extend beyond suppression of ETEC and appear mediated through altered development of the small intestine mucosa.