Milk thistle seed oil is still not a well-known edible oil. Silybum marianum (milk thistle), is present in several countries and is the only known representative of the genus Silybum. However, Silybum eburneum, which is an endemic plant in Spain, Kenya, Morocco, Algeria, and Tunisia, is considered a marginalized species. The present work is the first report that gives information on the lipid and phenolic profiles of Tunisian S. eburneum seed oil compared to those of Tunisian S. marianum seed oil. In addition, the antioxidant properties of these oils were determined with DPPH, FRAP, and KRL assays, and their ability to prevent oxidative stress was determined on human monocytic THP-1 cells. These oils are characterized by high amounts of unsaturated fatty acids; linoleic acid and oleic acid are the most abundant. Campesterol, sitosterol, stigmasterol, and β-amyrin were the major phytosterols identified. α-tocopherol was the predominant tocopherol found. These oils also contain significant amounts of phenolic compounds. The diversity and richness of Silybum marianum and Silybum eburneum seed oils in unsaturated fatty acids, phenolic compounds, and tocopherols are associated with high antioxidant activities revealed by the DPPH, FRAP, and KRL assays. In addition, on THP-1 cells, these oils powerfully reduced the oxidative stress induced by 7-ketocholesterol and 7β-hydroxycholesterol, two strongly pro-oxidant oxysterols often present at increased levels in patients with age-related diseases. Silybum marianum and Silybum eburneum seed oils are therefore important sources of bioactive molecules with nutritional interest that prevent age-related diseases, the frequency of which is increasing in all countries due to the length of life expectancy.