Among numerous biological activities, natural polyphenols are antioxidants widely distributed in plants capable of inhibiting lipid peroxidation, which belongs to the most serious degenerative cell processes. Positioning of antioxidants in lipid bilayers can provide an insight to the lipid-peroxidation inhibition at the molecular level. This work aims at determining the location and orientation of quercetin and its most representative (glucuronidated, methylated, and sulfated) metabolites in lipid bilayer via molecular dynamic simulations. We show that quercetin derivatives penetrate the lipid bilayer and that the depths of penetration depend on molecular charge and substitutional variations. In the presence of charged substituents (sulfates and glucuronidates), the molecule is pulled toward the lipid bilayer surface. The orientation also depends on substitution as H-bonds are formed between the polar head groups of the bilayer and the (i) OH groups, (ii) sugar, and (iii) sulfate moieties of the antioxidants. As flavonoids and their derivatives are preferentially localized in the lipid bilayer membrane or on the bilayer/water interface, they readily concentrate in a relatively narrow membrane region. Despite the low concentrations of flavonoids in food, their spatial confinement in the membrane greatly enhances their local concentration in this vital region, thus increasing their importance for in vivo biological activities including oxidative stress defense.