Activation of platelet integrin αIIbβ3, a key event for hemostasis and thrombus formation, is known to be mediated exclusively by inside-out signaling. We showed that inflammatory chemokines CX3CL1 and CXCL12 in previous studies, and CCL5 in this study, bound to the allosteric binding site (site 2) of vascular integrin αvβ3, in addition to the classical ligand binding site (site 1), and allosterically activated integrins independent of inside-out signaling. Since αIIbβ3 is exposed to inflammatory chemokines at increased concentrations during inflammation (e.g., cytokine/chemokine storm) and platelet activation, we hypothesized that these chemokines bind to and activate αIIbβ3 in an allosteric activation mechanism. We found that these chemokines bound to αIIbβ3. Notably, they activated soluble αIIbβ3 in 1 mM Ca2+ by binding to site 2. They activated cell-surface αIIbβ3 on CHO cells, which lack machinery for inside-out signaling or chemokine receptors, quickly (<1 min) and at low concentrations (1–10 ng/mL) compared to activation of soluble αIIbβ3, probably because chemokines bind to cell surface proteoglycans. Furthermore, activation of αIIbβ3 by the chemokines was several times more potent than 1 mM Mn2+. We propose that CCL5 and CXCL12 (stored in platelet granules) may allosterically activate αIIbβ3 upon platelet activation and trigger platelet aggregation. Transmembrane CX3CL1 on activated endothelial cells may mediate platelet–endothelial interaction by binding to and activating αIIbβ3. Additionally, these chemokines in circulation over-produced during inflammation may trigger αIIbβ3 activation, which is a possible missing link between inflammation and thrombosis.