Neurosurgery is considered the first-line treatment for almost all patients with acromegaly, particularly those with microadenomas or macroadenomas causing mass effects (such as vision loss). The preferred technique is Endoscopic Transsphenoidal Surgery, where the surgeon accesses the pituitary gland through the nasal cavity and sphenoid sinus. This approach avoids the need for a craniotomy and significantly reduces recovery time and surgical morbidity.

The goal of surgery is "biochemical cure," defined as the normalization of IGF-1 and the suppression of GH during an OGTT. Remission rates vary significantly based on tumor size and the experience of the surgeon; microadenomas have a remission rate of approximately 80–90%, while macroadenomas that have invaded the cavernous sinus are much harder to cure. For a breakdown of the surgical and post-operative management costs and trends, the Acromegaly Market analysis offers insights into the utilization of minimally invasive technologies. Even if a total cure is not achieved, "debulking" the tumor can improve the patient's response to subsequent medical therapies.

Post-operative monitoring is vital to detect complications such as "Diabetes Insipidus" (due to lack of ADH) or "Cerebrospinal Fluid (CSF) Leaks." Patients must also be monitored for hypopituitarism, where the removal of the tumor inadvertently damages the remaining healthy pituitary tissue, necessitating lifelong hormone replacement therapy for thyroid or adrenal function.