In this study, we explored the anti-inflammatory and antioxidant characteristics of the giant salamander peptide P3. We found that P3 enhances the resistance of RAW264.7 cells to lipopolysaccharide by modulating the mitogen-activated protein kinase/nuclear factor kappa-light-chain-enhancer of activated B cells (MAPK/NF-κB) signaling pathway. Specifically, P3 boosted the activation of MAPK, interleukin-6, and tumor necrosis factor alpha, while decreasing levels of inflammatory factors like interleukin-1β and nitric oxide. Given its potent antioxidant properties, we further examined impact of P3 in the Keap1-ARE-Nrf2 signaling pathway and its products. P3 increased the levels of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase, while reducing the concentrations of oxidation products like malondialdehyde and catalase. During in vitro digestion, the functional efficacy of P3 diminished. However, when combined with nano-starch (NS), NS-P3 demonstrated preserved functionality. Our findings indicate that P3 not only exhibits anti-inflammatory effects but also mitigates chronic oxidative stress damage. NS-P3 effectively safeguards the antioxidant capabilities of P3 during simulated digestion.