Silybum marianum contains flavonolignans, termed silymarin (SM), that are therapeutic agents for many inflammation-based diseases including atherosclerosis. Oxidation of human low-density lipoprotein was induced by CuSO4 or J774 macrophage cells and measured by the formation of thiobarbituric acid reactive substances (TBARS). SM was extracted by pressurized hot water (PHWE) or ethanol, and the effects of these extracts on TBARS formation were evaluated in comparison with those of SM preparations made from blending masses of individual flavonolignan standards in ratios identical to those of the water and ethanol extracts. Ethanol-extracted SM and its blended counterpart inhibited the generation of TBARS by 82% and 43%, respectively, at 150 μmol/L doses. TBARS levels in the presence of 150 μmol/L of the PHWE and its blended SM counterpart were reduced by 84% and 38%, respectively. Extracts from milk thistle fruit displayed higher protective effects than blended SM solutions of the same concentration with an identical compositional makeup. The appearance of degradation peaks in the water extract did not create any cytotoxic effects. Results of this study confirm that PHWE can be used to extract flavonolignans from milk thistle and that these extracts may possess therapeutic potential different from or beyond that of traditional organic solvent preparations.