Walnut meal, a key by-product of extracting oil from walnut kernels, contains abundant high-quality bioactive peptides. The molecular mechanism underlying the antioxidant effects of YWSPNDEQFR (YR-10), a novel antioxidant peptide found in walnut meal, remains unknown. The study examined the role of YR-10 in regulating oxidative damage induced by D-galactose in mice and by AAPH in HepG2 cells, focusing the JAK/STAT signaling pathway. Results analyses indicated that YR-10 enhanced gene expression in the NF-κB and TNF signaling pathways, while it suppressed the transcription of JAK, and STAT genes within the JAK/STAT pathway. Such modulation reduced the accumulation of peroxidative metabolites and inflammatory factors, thereby effectively decreasing oxidative damage. Furthermore, in vitro cell experiments and blocker inhibition experiments showed that the addition of YR-10 to AAPH-treated HepG2 cells produced an inhibitory effect on the expression of JAK and STAT proteins like that of JAK/STAT pathway blockers, thereby alleviating oxidative damage. In conclusion, YR-10 mitigated oxidative stress-induced damage by inhibiting the JAK/STAT pathway and enhancing antioxidant defenses.