Giant Grouper (Epinephelus lanceolatus) are one of the largest reef-dwelling bony fish housed in public aquaria. One challenge given their size and strength is safe restraint for medical purposes. Historically, some aquariums have achieved sedation with concentrated buffered tricane methanesulfonate (MS222) boluses underwater. However, this approach was not successful when our grouper required medical care for severe exophthalmia of the right eye. Sedation was achieved by administering ketamine (2.5 mg/kg) and medetomidine (0.128 mg/kg) IM with a pole syringe underwater. Six minutes after injection, the grouper floated to the surface and was moved to a floating pool where anesthesia was maintained with MS-222. Ultrasound revealed increased soft tissue echogenicity within the anterior and posterior ocular chambers. Enucleation was successfully performed and histopathology revealed chronic, severe, necrosuppurative, and granulomatous panophthalmitis that completely effaced the global architecture. While the grouper recovered from sedation, buoyancy was significantly compromised and she was unable to right herself. Diagnostics and supportive care were provided but her condition continued to decline and euthanasia was elected. Histopathology revealed a combination of hemorrhage, necrosis, and fibrocartilaginous metaplasia of the wall of the bulbus arteriosus that compromised luminal diameter and presumptively pliability of the cardiac chamber. While the exact effects of these changes on cardiac function, hemodynamic stability, and buoyancy control under anesthesia are not known, it is possible that it impacted recovery from the injectable protocol. Nonetheless, this injectable sedation protocol using ketamine and medetomidine represents an option for emergent cases in dire need of medical care.