The antioxidant and protective effects of phosvitin phosphopeptides (PPPs) in human neuroblastoma were studied. Phosvitin from chicken egg yolk was pretreated using high-temperature mild pressure (HTMP) conditions and then hydrolyzed using trypsin (T), Multifect 14L (M), and trypsin + Multifect 14L (TM) to prepare 4 PPPs treatments (HTMP, HTMP-T, HTMP-M, and HTMP-TM). The antioxidant and protective properties of PPPs were assessed using chemical analyses and human neuroblastoma (SH-SY-5Y) cells. All PPPs exhibited reducing power and radical scavenging, metal-chelating, β-carotene bleaching inhibitory, and lipid peroxidation inhibitory activities, but HTMP-TM had the highest antioxidant activity. HTMP-TM increased cell viability and reduced reactive oxygen species production and apoptosis in stressed (H₂O₂-treated) SH-SY-5Y cells. Additionally, HTMP-TM downregulated B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and caspase-3 expression but upregulated catalase expression in oxidatively stressed SH-SY-5Y cells. It was concluded that HTMP-TM exerted protective effects through their antioxidative and anti-apoptotic properties in oxidatively stressed SH-SY-5Y cells.