Reactive oxygen species (ROS) are potentially accountable for the growth of chronic inflammatory responses, which are responsible for the development of atherosclerosis, fibrosis, and cancer. Silymarin has been identified as a natural antioxidant that can be applied to reduce oxidative stress. However, the water solubility of silymarin is relatively low, which can affect its bioactivity when administered through oral ingestion. Therefore, a redox nanoparticle comprising silica moieties (siRNP) with approximately 120 nm in diameter has been designed to deliver silymarin orally. The siRNP nanoparticle possesses the nitroxide radical groups to scavenge ROS, and silica groups contributing to the stability of the nanoparticle in the gastric environment. Silymarin-loaded siRNP (SM@siRNP) showed impressive ability in scavenging hydroxyl radicals in vitro in comparison with free silymarin. The cytotoxic result indicates that SM@siRNP did not show any toxicity against macrophage cells, while silymarin caused cell death at the same concentration. Moreover, SM@siRNP highly protected the cells from the oxidative stress induced by ROS, and also significantly reduced the nitric oxide levels produced by lipopolysaccharide-triggered macrophage cells, which have a crucial function in the inflammatory process. The findings suggest that SM@siRNP could serve as an ideal nanocarrier for inflammatory-related disease.