Purpose To report a challenging Descemet Membrane Endothelial Keratoplasty (DMEK) case, complicated by intraoperative aqueous misdirection and spontaneous anterior chamber fibrin reaction. Methods A 70-year-old female affected by corneal edema due to Fuchs endothelial dystrophy underwent a triple procedure (cataract extraction - IOL implantation - DMEK surgery) in her left eye. This report illustrates the management of the intraoperative complications of aqueous misdirection syndrome and anterior chamber fibrin reaction. Results Despite the optimal management of the posterior pressure and the thorough removal of the fibrinous reaction during the case, the DMEK graft was not completely unfolded and centred at the end of the surgical procedure. Nonetheless, the patient showed good long-term anatomical and functional recovery: at the last follow-up (2 years after surgery), central corneal thickness was 526 µm with a best corrected visual acuity of 20/25 and an endothelial cell density of 1112 cell/mm². Conclusion Early recognition and prompt management of intraoperative aqueous misdirection syndrome and anterior chamber fibrin reaction during DMEK surgery is essential to ensure good functional and anatomical outcomes.