Inflammatory bowel disease (IBD) is a chronic inflammatory condition that can cause severe damage to the gastrointestinal tract leading to lower quality of life and productivity. Our goal was to investigate the protective effect of the soy peptide lunasin in an in vivo model of susceptibility to IBD and to identify the potential mechanism of action in vitro. In IL-10 deficient mice, oral administration of lunasin reduced the number and frequency of mice exhibiting macroscopic signs of susceptibility to inflammation and significantly decreased levels of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IL-18 by up to 95%, 90%, 90%, and 47%, respectively, in different sections of the small and large intestines. Dose-dependent decrease of caspase-1, IL-1beta, and IL-18 in LPS-primed and ATP-activated THP-1 human macrophages demonstrated the ability of lunasin to modulate the NLRP3 inflammasome. We demonstrated that lunasin can decrease susceptibility to IBD in genetically susceptible mice by exerting anti-inflammatory properties.