Background Platelet activation and thrombotic events characterizes COVID‐19. Objectives To characterize platelet activation and determine if SARS‐CoV‐2 induces platelet activation. Patients/Methods We investigated platelet activation in 119 COVID‐19 patients at admission in a university hospital in Milan, Italy, between March 18 and May 5, 2020. Sixty‐nine subjects (36 healthy donors, 26 patients with coronary artery disease, coronary artery disease, and seven patients with sepsis) served as controls. Results COVID‐19 patients had activated platelets, as assessed by the expression and distribution of HMGB1 and von Willebrand factor, and by the accumulation of platelet‐derived (plt) extracellular vesicles (EVs) and HMGB1+ plt‐EVs in the plasma. P‐selectin upregulation was not detectable on the platelet surface in a fraction of patients (55%) and the concentration of soluble P‐selectin in the plasma was conversely increased. The plasma concentration of HMGB1+ plt‐EVs of patients at hospital admission remained in a multivariate analysis an independent predictor of the clinical outcome, as assessed using a 6‐point ordinal scale (from 1 = discharged to 6 = death). Platelets interacting in vitro with SARS‐CoV‐2 underwent activation, which was replicated using SARS‐CoV‐2 pseudo‐viral particles and purified recombinant SARS‐CoV‐2 spike protein S1 subunits. Human platelets express CD147, a putative coreceptor for SARS‐CoV‐2, and Spike‐dependent platelet activation, aggregation and granule release, release of soluble P‐selectin and HMGB1+ plt‐EVs abated in the presence of anti‐CD147 antibodies. Conclusions Hence, an early and intense platelet activation, which is reproduced by stimulating platelets in vitro with SARS‐CoV‐2, characterizes COVID‐19 and could contribute to the inflammatory and hemostatic manifestations of the disease.