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SGGY, an antioxidant tetrapeptide identified from walnut protein hydrolysate in our previous study, has been suggested to possess the potential to alleviate oxidative stress in cells. In this paper, the neuroprotective effects of SGGY on H₂O₂-stimulated oxidative stress in SH-SY5Y cells and the underlying mechanisms were investigated. Results showed that SGGY alleviated H₂O₂-induced oxidative stress by decreasing the intracellular reactive oxygen species (ROS) level and altering the mitochondrial membrane potential (MMP), thereby inhibiting apoptosis and increasing cell viability. SGGY significantly restored antioxidant enzyme activities and reduced malondialdehyde (MDA) content accordingly. Moreover, SGGY promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and suppressed the H₂O₂-induced activation of JNK and p38 mitogen-activated protein kinases (MAPKs). Taken together, these results suggested that SGGY protected SH-SY5Y cells from H₂O₂-provoked oxidative stress by enhancing the ability of cellular antioxidant defense, and the possible mechanism involved MAPKs and Nrf2 signaling pathways.