The impact of ZnO as a feed additive on growth-performance and intestinal function of (ETEC) K88-infected piglets remains unclear. Fecal scores of piglets in ETEC group were significantly increased compared to control group. ETEC K88 significantly damages the small intestine, including a reduction in villus height in the jejunum, duodenum, and ileum, and a decrease in total superoxide dismutase activity in the jejunum and catalase activity in the ileum and jejunum. Compared to control group, ETEC K88 infection significantly elevated the mRNA level of gene and the level of ileal epithelial cell apoptosis. ZnO administration significantly alleviated these negative effects and improved the antioxidative capability of the ileum. Moreover, ZnO supplementation alleviated the imbalance of gut microbiota by restoring the reduced amount of and in the jejunum, in the ileum, and in the cecum, as well as the increased amount of total eubacteria in the ileum and in the cecum induced by the ETEC K88 infection. In conclusion, ZnO administration can reduce the diarrhea of piglets infected with ETEC K88 by reducing the structural damage of the intestine, attenuating intestinal oxidative stress and epithelial cell apoptosis, and modulating the gut microbiota.