BACKGROUND: Desmoplastic small round cell tumor is a rare sarcoma type with poor prognosis for which there is no standard of care. It primarily affects adolescents and young adults and treatment is both multimodal and challenging due to the aggressive nature of the disease. CASE PRESENTATION: we describe a case of a 27-year-old male who presented with hematuria and a five-centimeter mass on his bladder wall. His case details an especially challenging diagnosis as the pathology and IHC raised the suspicion for a poorly differentiated urothelial carcinoma until next-generation sequencing revealed the ESWR1::WT1 fusion gene rearrangement pathognomonic for desmoplastic small round cell tumor. After failing multiple lines of chemotherapy and also pembrolizumab, the patient was started on enfortumab-vedotin (EV), an antibody-drug conjugate targeting Nectin-4. Patient sustained partial response and documented disease control with clinical benefit for 23 months. Later, IHC staining of the tumor for nectin-4 was found to be moderately positive. CONCLUSION: This case report is the first documented usage of EV in the management of a desmoplastic small round cell tumor case and gives light to a new potential therapeutic strategy for this rare and aggressive tumor.