This study examined whether a commercially available fish-oil supplement offers protection from the acute effects of a high-fat meal (HFM) on endothelial function and arterial stiffness. An HFM causes acute impairments in endothelial function, whereas the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have a variety of cardioprotective effects. However, little is known about the efficacy of moderate fish-oil supplementation on the endothelial dysfunction induced by an HFM. Endothelial function (brachial artery flow-mediated dilation (FMD)), forearm blood flow (FBF), total hyperemia, central and peripheral blood pressure, and central artery stiffness were assessed in 20 healthy men (n = 10) and women (n = 10) at rest and 4 h after an HFM supplemented with either placebo or approximately 1 g EPA and DHA. Brachial artery FMD normalized for shear rate was significantly impaired (p = 0.033) following the HFM with placebo but remained unchanged compared with baseline following the HFM with the fish-oil supplement (p = 0.039; condition x time interaction). Resting FBF (p = 0.020) and total hyperemia (p = 0.014) were elevated following the HFM. All other vascular and hemodynamic measurements were unchanged in both trials. Commercially available fish-oil supplements taken with an HFM appear to preserve endothelial function following an HFM.