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Platelet hyperreactivity contributes to the pathogenesis of COVID‐19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID‐19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)2D3 on platelet hyperreactivity induced by SRAS‐CoV‐2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)2D3 attenuated platelet aggregation and Src‐mediated signaling. We further observed that 1,25(OH)2D3 attenuated spike protein‐potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)2D3 attenuated spike protein upregulated‐integrin αIIbβ3 outside‐in signaling such as platelet spreading and the phosphorylation of β3, c‐Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein‐stimulated platelet aggregation and integrin αIIbβ3 outside‐in signaling, the combination of PP2 and 1,25(OH)2D3 did not show additive inhibitory effects on spike protein‐potentiated platelet aggregation and the phosphorylation of β3, c‐Src and Syk. Thus, our data suggest that 1,25(OH)2D3 attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbβ3 outside‐in signaling. Significance Statement: Platelets exhibit enhanced platelet function and play a crucial role in thrombotic disorders in patients with COVID‐19. Several studies also explore the positive effects of vitamin D supplement on COVID‐19. However, the antiplatelet effect of vitamin D on spike protein‐potentiated platelet hyperreactivity is still unknown. In this study, we have observed that 1,25(OH)2D3 could attenuate spike protein‐potentiated platelet aggregation via inhibiting integrin αIIbβ3 outside‐in signaling in vitro. This study revealed the effects and mechanisms of 1,25(OH)2D3 on spike protein‐potentiated platelet aggregation. However, Clinical trials are needed to further confirm this effect. [ABSTRACT FROM AUTHOR]