This study investigated the effects of Porphyra yezoensis enzyme degradation extract (PYEDE) on the brain injuries and neurodegenerative diseases due to oxidative stress. We used in vitro antioxidant systems to verify the antioxidant potential of PYEDE. The results indicated that PYEDE alleviated weight loss and organ atrophy, reduced the levels of lipid peroxidation and protein carbonylation, and elevated glutathione (GSH) content in the serum and brains of the D-gal-induced aging model mice. PYEDE also renewed the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and total anti-oxidant capability (T-AOC) activities, downregulated the inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) levels, normalized the hippocampal neurons, and modulated multiple neurotransmitter systems by inhibiting the activities of acetylcholinesterase (AchE) and monoamine oxidase (MAO) in the upregulation of acetylcholine (Ach), dopamine (DA) and norepinephrine (NE) levels. Overall, PYEDE is a promising supplement for the alleviation of oxidative stress and age-associated brain diseases.