Platelets play important roles in vascular health. Activation of platelet may contribute to coagulation and inflammation. Evidence suggests circulating platelets are chronically activated in sickle cell disease (SCD) patients with steady state and further activated in vaso-occlusive crisis. However, the molecular basis of sickle platelet dysfunction remains obscure. Here, we used weighted gene coexpression network analysis combined with differentially expressed genes (DEGs) analysis to further investigate this basis. We found 57 DEGs were closely related to platelet dysfunction in SCD. Enrichment analysis showed that these 57 genes were mostly related to protein synthesis, adenosine triphosphate (ATP) synthase activity and inflammation, suggesting a hyperactivation status of platelets in SCD. We identified six hub genes from the 57 DEGs according to their Gene Significance value ranking, including CRYM, CCT6P1, SUCNR1, PRKAB2, GSTM3 and FCGR2C. Altogether, our results offered some new insight into platelet activation and identified novel potential targets for antiplatelet therapy in SCD.