In this study, the effect of polyphenolic extracts from cowpea (Vigna unguiculata) on global gene expression in bovine peripheral blood was investigated. Blood collected from Holstein-Friesian cows (n = 10) was treated with 10 μg/mL of cowpea phenolic extract (CPE) and subsequently used for transcriptional profiling using the Agilent bovine (v2) 4 × 44 K array. Calculation of fold change in gene expression and pathway analysis was conducted using the GeneSpring GX software 13.0. Real-time quantitative PCR was performed to validate the microarray data. Phenolic extracts of cowpea impacted global gene expression and resulted in 3170 differentially expressed genes (p < .05); 1716 genes were upregulated and 1454 genes were downregulated. Exposure to CPE impacted 66 pathways (p < .05) including the Wnt signalling pathway, Toll-like receptor pathway, inflammation response pathway, MAPK cascade pathway, prostaglandin synthesis and regulation pathway, cell cycle pathway, insulin signalling pathway, and the adipogenesis pathway. Expression of immune markers such as CD40, CD68, Toll-like receptors, and Wnt signalling changed. Exposure to CPE modulated expression of genes associated with immunity and homeostasis. Transcriptional profiles of the response to polyphenols may aid in the design of targeted diets to influence animal production and health and thus requires further study