Our major findings are (i) expression of ACKR3 on platelets in patients with symptomatic CAD is associated with clinical prognosis, (ii) genetic deficiency of platelet ACKR3 promotes platelet activation and tissue injury in ischemic myocardium and brain; (iii) loss of platelet ACKR3 aggravates tissue inflammation and systemic thrombo-inflammation; (iv) activation of platelet-ACKR3 mediates inhibitory effects on platelet activation and thrombus formation, and (v) attenuates tissue injury in ischemic myocardium and brain. Here, ACKR3 is linked to coronary artery disorder.