The initial contact with blood and its components, including plasma proteins and platelets, directs the body's response to foreign materials. Natural scaffolds of extracellular matrix or fibrin contain fibrils with nanoscale dimensions, but how platelets specifically respond to the topography and architecture of fibrous materials is still incompletely understood. Here, planar and nanofiber scaffolds are fabricated from native fibrinogen to characterize the morphology of adherent platelets and activation markers for phosphatidylserine exposure and α‐granule secretion by confocal fluorescence microscopy and scanning electron microscopy. Different fibrinogen topographies equally support the spreading and α‐granule secretion of washed platelets. In contrast, preincubation of the scaffolds with plasma diminishes platelet spreading on planar fibrinogen surfaces but not on nanofibers. The data show that the enhanced interactions of platelets with nanofibers result from a higher locally accessible surface area, effectively increasing the ligand density for integrin‐mediated responses. Overall, fibrinogen nanofibers direct platelets toward robust adhesion formation and α‐granule secretion while minimizing their procoagulant activity. Similar results on fibrinogen‐coated polydimethylsiloxane substrates with micrometer‐sized 3D features suggest that surface topography could be used more generally to steer blood‐materials interactions on different length scales for enhancing the initial wound healing steps.