BACKGROUND: Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ews-ing Sarcoma by interaction with RNA molecules. AIMS: The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma. OBJECTIVE: The current study explores the complexity of EWSR1 structure and its conforma-tional interactions with RNA in relation to Ewing sarcoma. METHODS: Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes. RESULTS: The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression. CONCLUSION: Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.