We show that the expression and activity of the arginine methyltransferases PRMT1 and PRMT5 are elevated in Ewing sarcoma and that inhibition of PRMT1 or PRMT5 with pre-clinical inhibitors leads to growth arrest and apoptosis that is dependent on the expression of the driver oncogene EWSR1::FLI1. Mechanically, we show that PRMT1 and PRMT5 inhibitors promote DNA damage, and that PRMT5 inhibitors synergise with the PARP inhibitor olaparib to induce elevated DNA damage and reduced cell viability. This evidence concerns the gene EWSR1 and Ewing sarcoma.