In our previous study, defatted walnut meal hydrolysate (DWMH) could attenuate D-galactose-induced acute memory deficits in vivo, and 6 potent active peptides including WSREEQ, WSREEQE, WSREEQEREE, ADIYTE, ADIYTEEAG and ADIYTEEAGR were identified. The aim of this study was to investigate the possible mechanism underlying their neuroprotective effects on glutamate-induced apoptosis in PC12 cells and their digestive stability. Results showed that all these peptides could attenuate the reduction of cell viability caused by glutamate in PC12 cells, especially WSREEQEREE and ADIYTEEAGR. The addition of Arg residue in WSREEQEREE and ADIYTEEAGR might be the potential reason for their stronger protective effects. Additionally, these two peptides possibly protected PC12 cells against glutamate-induced apoptosis via activating intracellular antioxidant defence (superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) through Kelch-like ECH-associated protein 1 (Keap1) inhibition, inhibiting ROS production, Ca2+ influx and mitochondrial membrane potential (MMP) collapse as well as regulating the expression of apoptosis-related proteins (Bax and Bcl-2). This might be due to the presence of Trp, Tyr and Arg in these two peptides. However, encapsulation of WSREEQEREE and ADIYTEEAGR should be considered based on their digestive sensibility during in vitro gastrointestinal digestion.