An adult female European cuttlefish (Sepia officinalis) from a public aquarium presented with an eruptive skin lesion of the dorsal mantle. Radiographs, hemolymph collection, and excisional biopsy were performed using anesthesia with ethanol 1.5–3% in seawater. Elastic and freely mobile skin permitted closure with minimal tension following wide excision around the lesions, which did not appear to penetrate deep to the underlying cuttlebone. Biopsy revealed hemocyte granulomas surrounding thin, septate, infrequently branching fungal hyphae, and culture yielded Cladosporium sp. Itraconazole was administered postoperatively in food items. The cuttlefish recovered to normal feeding and activity levels with complete surgical site healing. Two months following the procedure, the animal was found dead in exhibit. Histopathologic examination revealed multisystemic fungal infection.