Ceramides are a class of sphingolipids which have recently been shown to be better cardiovascular disease (CVD) risk predictors than traditional CVD risk biomarkers. Tyrosol (TYR) is a dietary phenolic compound known to possess cardioprotective effects per se or through its in vivo active metabolite hydroxytyrosol. The purpose of this study was to evaluate the effects of the co-administration of white wine (WW) and TYR on circulating levels of ceramides and other lipids in humans at high CVD risk. Volunteers underwent a randomized controlled crossover clinical trial (4-week duration per intervention) with three different interventions: control, WW, and WW enriched with a capsule of TYR (WW + TYR). Endothelial function cardiovascular biomarkers and plasma lipidomic profile were assessed before and after each intervention. It was found that the WW + TYR intervention resulted in lower levels of three ceramide ratios, associated with an improvement of endothelial function (Cer C16:0/Cer C24:0, Cer C18:0/Cer C24:0, and Cer C24:1/Cer C24:0), when compared to the control intervention. Moreover, WW + TYR was able to minimize the alterations in plasma diacylglycerols concentrations observed following WW. Overall, the results obtained show that the antioxidant TYR administered with WW exerts beneficial effects at the cardiovascular level, in part by modulating blood lipid profile.