This study aimed to investigate the anti-inflammatory effect of walnut-derived peptide LPLLR (LP-5) in oxidative stress-induced Caco-2 cells and model mice. The results showed that LP-5 significantly increased the activities of CAT and SOD, while decreased the levels of MDA both in vitro and in vivo. The oxidative stress signaling was regulated by promoting Nrf2 nuclear transfer, up-regulating HO-1 expression, and down-regulating Keap1 expression. As demonstrated by molecular docking, LP-5 could effectively bind Keap1. Additionally, LP-5 effectively inhibited the activation of the NLRP3 inflammasome via down-regulating the expression of NLRP3, ASC, and caspase-1, significantly reducing the release of inflammatory cytokines, including IL-18, IL-1β, and TNF-α, thereby preventing cell apoptosis. Moreover, LP-5 increased the production of IL-10 and decreased the levels of iNOS and COX-2 in Caco-2 cells. These data suggested that LP-5 ameliorated oxidative stress-mediated inflammation by inhibiting the NLRP3 inflammasome by activating Nrf2/Keap1 signaling.