Our patented protease A–digested crude chalaza hydrolysates (
CCH
) show antioxidant abilities in vitro. The prophylactic effects of CCH on cognitive dysfunction and brain oxidative damages were investigated via a D-galactose (
DG
)–injected mouse model in this study. Fifty-four mice were randomly divided into the following: (1) CON, 0.1 mL 0.9% saline (subcutaneous injection [
SC
] on the back)+distilled water (oral gavage); (2) DG, 100 mg/kg BW/day D-galactose (Bio-Serv Co., Flemington, NJ, USA) (SC on the back)+distilled water (oral gavage); (3) DG_LCH, 100 mg/kg BW/day D-galactose (SC on the back) + 50 mg CCH/kg BW/day in 0.1 ml distilled water (oral gavage); (4) DG_MCH, 100 mg/kg BW/day D-galactose (SC on the back) + 100 mg CCH/kg BW/day (oral gavage); (5) DG_HCH, 100 mg/kg BW/day D-galactose (SC on the back) + 200 mg CCH/kg BW/day (oral gavage); (6) DG_AG, 100 mg/kg BW/day D-galactose (SC on the back) + 100 mg aminoguanidine hydrochloride/kg BW/day (oral gavage). The experiment lasted for 84 D. CCH, containing antioxidant-free amino acids and anserine, restored (
P
< 0.05) DG-injected memory injury in the Morris water maze test and attenuated the neuronal degenerations and nucleus shrinkages in the dentate gyrus area. CCH supplementation also reduced amyloid β-peptide protein levels and accumulation of advanced glycation end products (AGE) in the brain of DG-injected mice, whereas the brain antioxidant capacity was reversed (
P
< 0.05) by supplementing CCH. Furthermore,
AGE receptor
(
RAGE
),
NFκb
,
IL-6
, and
TNF-α
gene expressions were downregulated (
P
< 0.05) by supplementing CCH. Therefore, CCH show prophylactic effects on the development of oxidative stress-induced cognitive dysfunction.