Many polyphenols, such as hydroxytyrosol (HT), have been recognized for their antioxidant and cardiovascular (CV) health benefits. To address the efficacy of HT, the present study aimed to identify the relevant mechanisms, associated with high-CV risk. Plasma unbiased multi-omics data were compared among two subgroups -HT responders and non-responders patients- and in a mice model. Lipid metabolism and proteomic responses were heterogeneous within two distinct ̶ responder and non-responder ̶ subgroups, associated mainly with thrombotic and hemostatic signals. The correlations between classical CV biomarkers, proteins, and metabolites offer a more comprehensive representation of the glutathione and coagulation pathways affected by HT treatment.