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Scope: Collagen hydrolysates have been reported with a variety of biological activities. The previous study has separated and identified a series of Hyp-Gly containing antiplatelet peptides from collagen hydrolysates from Salmo salar. But the target and underlying mechanism in platelets remains unknown. Methods and results: In this study, peptide OGEFG (OG-5) inhibits platelet aggregation especially induced by 2MeS-ADP and attenuates tail thrombosis formation by 30% in a dose-dependent manner, via apparent antagonism effects on P 2 Y 12 receptors to regulate G𝜷𝜸i-PI3K-Akt signaling and G𝜶i-cAMP-VASP signaling is demonstrated. The molecular docking results also reveal a strong binding energy with the P 2 Y 12 receptor of peptide OG-5 (−10.70 kcal mol −1 ). In vitro study suggests that OG-5 inhibited the release of inflammatory cytokines in endothelial cells and macrophage cells, migration of vascular smooth muscle cell induced by ADP, which is highly released in ApoE -/mice. Long-term administration of OG-5 significantly reduces atherosclerotic plaque formation without side effects in ApoE -/mice, exhibiting a comparable effect with aspirin. Conclusion: These results reveal that collagen hydrolysates with OG-containing peptides have potential to be developed as an effective diet supplement to prevent the occurrence of atherogenesis and thrombotic disease.