5-fluorouracil (5-FU) is a fluoropyrimidine widely used in oncology that is known for its cardiotoxicity, mainly in the form of coronary vasospasm. Non-coronary vascular complications remain rare. We report the case of a 78-year-old patient treated for muscle-invasive urothelial bladder carcinoma (pT2) with a trimodality approach including macroscopically complete transurethral resection of the bladder, followed by concurrent chemoradiotherapy with mitomycin C and 5-FU. On the third day of the second cycle of continuous 5-FU infusion, the patient developed acute thoraco-epigastric pain radiating to the back, associated with hemodynamic and neurological signs. Computed tomography angiography revealed an acute Stanford type A aortic dissection. 5-FU may induce diffuse endothelial injury leading to coronary vasospasm and tissue ischemia. More diffuse injury involving the vasa vasorum may promote medial ischemia, thereby weakening the aortic wall and predisposing to dissection. Although a causal relationship cannot be formally established, the temporal association and the absence of an alternative cause support a possible role of 5-FU. This case highlights the need to promptly consider aortic dissection in patients presenting with unusual chest or back pain occurring under fluoropyrimidine therapy.