Binding of fibrinogen to platelet integrin α_IIbβ₃ mediates platelet aggregation, and thus inhibition of α_IIbβ₃ represents a powerful therapeutic strategy in cardiovascular medicine. However, the currently used inhibitors of α_IIbβ₃ demonstrate several adverse effects like thrombocytopenia and bleeding, which are associated with their property to bind to non‐activated α_IIbβ₃. To circumvent these problems, we designed blocking single‐chain antibody‐fragments (scFv) that bind to α_IIbβ₃ exclusively in its activated conformation. Two naïve phage libraries were created: a natural phage library, based on human lymphocyte cDNA, and a synthetic library, with randomized V_HCDR3. We performed serial rounds of subtractive panning with depletion on non‐activated and selection on activated α_IIbβ₃, which were provided on resting and ADP‐stimulated platelets and CHO cells, expressing wild‐type or mutated and thereby activated α_IIbβ₃. In contrast to isolated, immobilized targets, as generally used for phage display, this unique cell‐based approach for panning allowed the preservation of functional integrin conformation. Thereby, we obtained several scFv‐clones that demonstrated exclusive binding to activated platelets and complete inhibition of fibrinogen binding and platelet aggregation. Interestingly, all activation‐specific clones contained an RXD pattern in the HCDR3. Binding studies on transiently expressed point mutants and mouse‐human domain‐switch mutants of α_IIbβ₃ indicate a binding site similar to fibrinogen. In conclusion, we generated human activation‐specific scFvs against α_IIbβ₃, which bind selectively to activated α_IIbβ₃ and thereby potently inhibit fibrinogen binding to α_IIbβ₃ and platelet aggregation.