The aim of this intervention study was to measure genome-wide postprandial gene expression in human blood cells after the ingestion of a single serving of milk, to identify the downstream physiological processes regulated by the differentially expressed genes, and to use this gene expression signature as a reference to compare it with the response following the ingestion of a transformed dairy product, namely, yogurt. We conducted a randomized, controlled, single-blinded, crossover study on six healthy male individuals. After an overnight fast, 540 g of milk or yogurt was ingested by the subjects. Blood samples were collected before (0 h) and after (2 h/4 h/6 h) ingestion, and the blood cell transcriptome was analyzed using a linear kinetic analysis that increases the statistical power of the study. The differentially expressed transcripts identified after the ingestion of milk (575 transcripts) and yogurt (625 transcripts) modulated similar biological processes. In particular, genes involved in protein biosynthesis and mitochondrial activities followed biphasic kinetics being down-regulated at 2 h and more pronouncedly up-regulated at 6 h. The opposite kinetics were observed for inflammatory and apoptotic processes during the same time frame. The human blood cell transcriptome appeared to be specifically modulated by specific nutrients present in bovine milk, a property that was further modified when milk was fermented to yogurt. The coordinated changes in postprandial expression of genes involved in basic biological processes suggest that postprandial blood cell transcriptomics may allow insight into the nutritional effects of selected foods in the prevention or development of chronic metabolic and inflammatory disorders.