This study was conducted to characterize the effects of infection with a pathogenic F-18 Escherichia coli and 3 different plant extracts on gene expression of ileal mucosa in weaned pigs. Weaned pigs (total = 64, 6.3 ± 0.2 kg BW, and 21-d old) were housed in individual pens for 15 d, 4 d before and 11 d after the first inoculation (d 0). Treatments were in a 2 × 4 factorial arrangement: with or without an F-18 E. coli challenge and 4 diets (a nursery basal, control diet [CON], 10 ppm of capsicum oleoresin [CAP], garlic botanical [GAR], or turmeric oleoresin [TUR]). Results reported elsewhere showed that the plant extracts reduced diarrhea in challenged pigs. Total RNA (4 pigs/treatment) was extracted from ileal mucosa of pigs at d 5 post inoculation. Double-stranded cDNA was amplified, labeled, and further hybridized to the microarray, and data were analyzed in R. Differential gene expression was tested by fitting a mixed linear model in a 2 × 4 factorial ANOVA. Bioinformatics analysis was conducted by DAVID Bioinformatics Resources 6.7 (DAVID; National Institute of Allergy and Infectious Diseases [NIAID, NIH], http://david.abcc.ncifcrf.gov). The E. coli infection altered (P < 0.05) the expression of 240 genes in pigs fed the CON (148 up- and 92 down-regulated). Compared with the infected CON, feeding CAP, GAR, or TUR altered (P < 0.05) the expression of 52 genes (18 up, 34 down), 117 genes (34 up- and 83 down-regulated), or 84 genes (16 up- and 68 down-regulated), respectively, often counteracting the effects of E. coli. The E. coli infection up-regulated (P < 0.05) the expression of genes related to the activation of immune response and complement and coagulation cascades, but down-regulated (P < 0.05) the expression of genes involved in protein synthesis and accumulation. Compared with the CON, feeding CAP and GAR increased (P < 0.05) the expression of genes related to integrity of membranes in infected pigs, indicating enhanced gut mucosa health. Moreover, feeding all 3 plant extracts reduced (P < 0.05) the expression of genes associated with antigen presentation or other biological processes of immune responses, indicating they attenuated overstimulation of immune responses caused by E. coli. These findings may explain why diarrhea was reduced and clinical immune responses were ameliorated in infected pigs fed plant extracts. In conclusion, plant extracts altered the expression of genes in ileal mucosa of E. coli-infected pigs, perhaps leading to the reduction in diarrhea reported previously.