Polyphenols are a class of bioactive plant compounds with health-promoting properties, however, the interactions between polyphenols and pathogen infection and their cumulative impact on inflammation and metabolic health are not well understood. Here, we investigated if a subclinical parasitic infection modulates the hepatic response to dietary polyphenol supplementation in a porcine model. Pigs were fed a diet with or without 1% grape proanthocyanidins (PAC) for 28 days. During the final 14 days of the experiment, half the pigs in each dietary group were inoculated with the parasitic nematode Ascaris suum. Serum biochemistry was measured and hepatic transcriptional responses were determined by RNA-sequencing coupled with gene-set enrichment analysis. A. suum infection resulted in reduced serum phosphate, potassium, sodium, and calcium, and increased serum iron concentrations. In uninfected pigs, PAC supplementation markedly changed the liver transcriptome including genes related to carbohydrate and lipid metabolism, insulin signaling, and bile acid synthesis. However, during A. suum infection, a separate set of genes were modulated by dietary PAC, indicating that the polyphenol-mediated effects were dependent on infection status. A. suum infection strongly influenced the expression of genes related to cellular metabolism, and, in contrast to the effects of PAC, these changes were mostly identical in both control-fed and PAC-fed pigs. Thus, the hepatic response to infection was mostly unaffected by concurrent polyphenol intake. We conclude that the presence of a commonly occurring parasite substantially influences the outcome of dietary polyphenol supplementation, which may have important relevance for nutritional interventions in populations where intestinal parasitism is widespread.