A 16-year-old warmblood mare was referred with a progressive history of behavioral changes and left-sided blindness. Following neuroanatomical localization to the forebrain, magnetic resonance imaging of the head revealed a well-delineated, 4.5 cm in diameter, round pituitary mass causing marked compression of the midbrain and optic chiasm. Euthanasia was recommended but declined by the owners. Veterinary specialists and a human neurosurgeon collaboratively prepared for surgical case management. A novel navigated transmandibular lateral transsphenoidal approach was developed to access the region of the sella turcica and practiced on cadaver specimens. The horse was anesthetized and placed in sternal recumbency with the head above the heart line. Using a cone beam computed tomography (CBCT)-coupled navigation system, a navigated pin traversing the vertical ramus of the mandible and the lateral pterygoid muscle was placed in a direct trajectory to the predetermined osteotomy site of the basisphenoid bone. A safe corridor to the osteotomy site was established using sequential tubular dilators bypassing the guttural pouch, internal and external carotid arteries. Despite the use of microsurgical techniques, visualization of critical structures was limited by the long and narrow working channel. Whilst partial resection of the mass was achieved, iatrogenic trauma to the normal brain parenchyma was identified by intraoperative imaging. With consent of the owner the mare was euthanized under the same general anesthesia. Post-mortem magnetic resonance imaging and gross anatomical examination confirmed partial removal of a pituitary adenoma, but also iatrogenic damage to the surrounding brain parenchyma, including the thalamus.