The goal of this study was to evaluate the effect of an optimized plant polyphenol (PP) mixture consisting of polyphenols extracted from apples, grape seeds, green teas and olive leaves on the systemic antioxidant capacity in piglets orally challenged with Escherichia coli (E. coli). A total of 24 piglets were weaned at 28 days and allocated to 4 groups for a 42-d experiment with a 2 × 2 factorial design comparing different dietary treatments [a basal diet without (CTR) or with 0.1% of the optimized PP mixture (PP)] and oral E. coli challenges on days 21 and 25 (saline or E. coli). On days 25, 27 and 34 of the trial, one piglet from each pen was selected for blood sampling. The E. coli challenge decreased the gain-to-feed ratio (G:F) from day 21 to day 42 (P < 0.10), reduced plasma superoxide anion (SAIC) and hydroxyl radical (HRIC) inhibiting capacities, and increased the plasma ceruloplasmin content on day 27 (P < 0.10). PP supplementation increased the G:F ratio from day 21 to day 42 (P < 0.10). Compared with the CTR diet, PP supplementation increased plasma GSH-Px activity on day 25 and plasma T-AOC activity on day 27 (P < 0.10), and dietary PP increased plasma SAIC on day 27 and plasma HRIC on day 34 (P < 0.10). These results suggest that PP supplementation may improve the antioxidant status of post-weaning piglets and counteract some of the negative effects that occur when piglets are challenged with E. coli.