Despite advances in stent technology for vascular interventions, in‐stent restenosis (ISR) remains a main complication. The corrosion of cobalt–chromium (CoCr) alloy coronary stents has been identified to be associated with ISR, whereas its role in ISR has not been elucidated. In the current work, CoCr nanoparticles, simulated corrosion products of CoCr alloy, were used to investigate their effect on the endothelial cells. It has been demonstrated that the cell viability declines and the cell membrane is damaged, indicating the cytotoxicity of CoCr nanoparticles. The expression of GRP78, CHOP, and cleaved‐caspase12 proteins has increased when exposed to CoCr nanoparticles, suggesting that CoCr nanoparticles induced cell apoptosis through endoplasmic reticulum (ER) stress‐mediated apoptotic pathway. An increased release of adhesion and inflammatory mediators was also induced by CoCr nanoparticles, including ICAM‐1, VCAM‐1, IL‐1β, IL‐6, and TNF‐α. Our results demonstrated that CoCr nanoparticles could trigger apoptosis, adhesion, and inflammation. These findings indicated potential damaging effects of CoCr nanoparticles on the vascular endothelium, which suggested corrosion of CoCr alloy may promote the progression and development of ISR.