Apolipoprotein E (APOE) is glycoprotein involved in lipid metabolism and homeostasis. The three main APOE isoforms (APOE2, APOE3, and APOE4)—that differ in the number of sulfhydryl groups—exhibit structural differences that affect their functions, including lipoprotein interaction and antioxidant capacities. APOE4 is particularly associated with increased oxidative stress due to its reduced ability to neutralize lipid peroxidation byproducts like 4-hydroxynonenal (4-HNE). The presence of APOE4 in the brain, that is highly susceptible to oxidative damage due to its lipid-rich composition and high oxygen consumption, along with APOE4 promoting β-amyloid aggregation and tau hyperphosphorylation, increases Alzheimer’s disease risk. APOE4-related oxidative stress also enhances LDL oxidation and endothelial dysfunction, increasing atherosclerosis risk. Given these effects, antioxidant strategies, including dietary polyphenols, vitamins, and novel delivery systems, such as liposome-based therapies, have been explored as potential interventions. While some antioxidants show promising results in mitigating oxidative damage and disease progression, their efficacy is influenced by bioavailability, blood–brain barrier permeability, and interactions with APOE isoforms. Future therapeutic approaches should consider APOE genotype to enhance antioxidant efficacy in neurodegenerative and cardiovascular diseases.