Dry beans (Phaseolus vulgaricus) are gaining recognition as an exceptional plant-based protein source, with studies showing reduced risks of cardiovascular diseases, obesity, and diabetes due to their bioactive compounds. Despite being one of the highest produced legumes in the US, Great Northern beans (GNB) have lower consumption rates than other beans. This study utilized an innovative aqueous-based isolation method to identify bioactive compounds in GNB. The <3 kDa fraction reduced TNF-α-induced inflammatory and oxidative stress in vascular endothelial cells (HUVEC). Comprising γ-glutamyl peptides, dipeptides rich in hydrophobic and aromatic amino acids, and phenolic compounds, the bioactive <3 kDa fraction's effects were preserved even after simulated gastrointestinal digestion. These findings suggest that GNBs' bioactive compounds may exert systemic inhibition against vascular inflammation and oxidative stress, presenting promising potential for preventing vascular diseases. Further research is required to incorporate this bioactive fraction into foods or developing novel GNB based foods could potentially enhance the consumption of GNB as well support the cardiovascular health of the consumers.