A 2 x 3 factorial experiment was performed to evaluate the effects of seaweed extract (SWE) supplementation to sows and/or piglets after weaning on factors affecting small intestinal morphology, microbiology, and mucosal gene expression in weaned piglets experimentally challenged with enterotoxigenic Escherichia coli (ETEC). The 6 dietary treatments (n = 12 pigs/treatment) were based on lactation and postweaning diets: 1) basal-fed sows and basal-fed pigs (B-B), 2) basal-fed sows and SWE-supplemented pigs (B-SWE), 3) basal-fed sows and ZnO-supplemented pigs, 4) SWE-supplemented sows and basal-fed pigs (SWE-B), 5) SWE-supplemented sows and SWE-supplemented pigs (SWE-SWE), and 6) SWE-supplemented sows and ZnO-supplemented pigs. On Day 10 after weaning, pigs were challenged with 10(8) cfu ETEC, and pigs were euthanized on Day 12 after weaning. Intestinal tissue and digesta samples were taken for histological, gene expression, and microbiological analysis. There was an interaction between maternal and postweaning supplementation on small intestinal morphology in the jejunum. Pigs from the B-B treatment group had larger crypts and a lower villous height (VH): crypt depth (CD) ratio compared with the SWE-B treatment group. However, there was no effect of maternal SWE supplementation on small intestinal morphology when a SWE-or ZnO-supplemented diet was offered after weaning. Postweaning SWE supplementation resulted in a reduced expression of genes for heat-labile enterotoxins from ETEC (log gene copy numbers [GCN]) in cecal and colonic digesta (P < 0.05). An interaction was observed between maternal and postweaning SWE supplementation for enteroaggregative E. coli heat-stable enterotoxin 1 (EAST1) toxin log GCN in colonic digesta (P < 0.05). Pigs from the SWE-SWE treatment group had reduced EAST1 enterotoxin log GCN in colonic digesta compared with pigs from the B-SWE treatment group (P < 0.05). Postweaning supplementation with ZnO resulted in reduced mRNA expression of IL-8 in both ileal and colonic tissue and IL-1 alpha in colonic tissue (P < 0.05). In conclusion, SWE supplementation after weaning reduced CD, improved the VH: CD ratio, and reduced the log GCN of ETEC-associated enterotoxins in cecal and colonic digesta. Postweaning ZnO supplementation resulted in reduced expression of proinflammatory cytokines in ileal and colonic tissue.