Platelet apoptosis is crucial for initiating atherothrombosis and is primarily induced by circulating oxidized lipids in oxidized low-density lipoprotein (ox-LDL) particles under hyperlipidemic conditions. Panax notoginseng has excellent medicinal and food dual-use characteristics. P. notoginseng saponins (PNS), the primary active ingredients extracted from the roots of P. notoginseng, are widely used as nutritional supplements owing to their multiple health benefits. In this study, we investigated the efficacy of PNS in platelet apoptosis under hyperlipidemic conditions in vitro and in vivo. In vitro assays demonstrated that PNS attenuated platelet mitochondrial dysfunction (loss of mitochondrial membrane potential) and subsequent apoptosis (caspase-9/-3 activation and phosphatidylserine exposure) in ox-LDL-stimulated human platelets. Mechanistically, PNS activated cAMP/PKA signaling, leading to decreased NOX2-mediated oxidative stress, and the resultant inhibition of platelet apoptosis. Moreover, 12-week supplementation of PNS (0.02% diet) in hyperlipidemic C57BL/6J mice also significantly alleviated platelet mitochondrial dysfunction and apoptosis in vivo. Studies using pharmacological inhibitors of PKA and NOX2 demonstrated that the efficacy of PNS on platelet dysfunction in mice was primarily modulated by the up-regulation of cAMP/PKA signaling and the resultant inhibition of NOX2-dependent oxidative stress. Thus, these results suggest that PNS attenuate oxidative stress-mediated platelet apoptosis under hyperlipidemic conditions by up-regulating the cAMP/PKA signaling pathway in vitro and in vivo. Our study elucidated a possible novel strategy of involving the use of PNS to prevent atherothrombosis in hyperlipidemia.