Nutraceuticals are food constituents with potential health benefits beyond their nutritional value. In vitro and In vivo studies suggest a protective effect of nutraceuticals against chronic diseases, but the results are not fully supported by clinical evidence. Nutraceuticals are generally recognized as safe at dietary doses; however, they are often consumed at higher doses in the form of nutritional supplements. Exposure to supra-dietary doses of nutraceuticals is of toxicological concern, particularly because some substances may cause genomic changes in target tissues. Here, we assessed the effect of four nutraceuticals, resveratrol (a polyphenol present in grapes and berries), quercetin (a flavonol found in many fruits, vegetables, leaves and grains), astaxanthin (a keto-carotenoid found in microalgae, yeast, many fishes and crustaceans), and epigallocatechin gallate (a polyphenol present in tea and in various vegetables), in two human primary cell types, cryopreserved hepatocytes and coronary artery endothelial cells (HCAECs), using a multi-step systems biology approach combining (STEP 1) real-time cell viability measurements with (STEP 2) a panel of high-content screening (HCS) endpoints and (STEP 3) gene expression changes analysis based on computable biological network models.