On 16 October 1846, after administration of ether by Morton, MGH Chief of Surgery, John Collins Warren, painlessly removed a tumor from the neck of a local printer, Edward Gilbert Abbott.

In the time since the accident, the arm had grown a "deathly gray", but grew steadily pink as the surgery progressed and blood vessels were reattached.

Malt, "was apply techniques we've known about for a long time and simply never had occasion to correlate before...The astonishing thing was not the newness of the operation but the teamwork—the way 12 doctors with expert skills, distinguished a collection of authorities as you could find anywhere, were willing to stand by and feed the incomparable extent of their knowledge to me, for no gain other than to know they had contributed.

"[15] In April 2019, MGH received a $200 million gift from Cambridge entrepreneur Phillip "Terry" Ragon to endow a permanent vaccine research center.

The hospital handles around 1.5 million outpatient visits each year at its main campus, as well as its seven satellite facilities in Boston at Back Bay, Charlestown, Chelsea, Everett, Revere, Waltham and Danvers.

[23] Architect Hisham N. Ashkouri, working in conjunction with Hoskins Scott Taylor and Partners, provided the space designs and schematics for the pediatrics, neonatal intensive care, and in-patient related floors, as well as the third-floor surgical suites and support facilities.

The hospital provides comprehensive pediatric specialties and subspecialties to patients aged 0–21[30][31] throughout Boston and the wider Massachusetts.

[32] Massachusetts General Hospital for Children also features the only ACS-verified Level 1 Adult and Pediatric Trauma Center in the state.

[34] The hospital has an American Academy of Pediatrics verified level III neonatal intensive care unit that has a capacity of 18 bassinets.

[37] As of 2021, Massachusetts General Hospital for Children has placed nationally in 5 ranked pediatric specialties on U.S. News & World Report.

[45] In 2019, 55 scientists from MGH were listed in Clarivate Analytics' Web of Science annual Highly Cited Researchers Report.

As part of the Mass General Hospital System, the Cancer Center extends throughout New England and has several different community locations to receive treatment.

In February 2009, the Phillip T. and Susan M. Ragon Institute of immunology was founded to bolster research into creating vaccines and other therapies for acquired immune system conditions, chiefly AIDS.

[52] The Recovery Research Institute was created in 2013 by John F. Kelly, the first endowed professor of Addiction Medicine at Harvard Medical School.

[55] The institute also created the Addictionary, the first-ever glossary of addiction-related terms and a system for stigmatized terminology alerts.

In 2015, MGH Home Base Program became a founding partner of the Warrior Care Network health system focused on treating post-traumatic stress disorder (PTSD) in veterans, along with partners Emory Healthcare, Rush University Medical Center, UCLA Health and Wounded Warrior Project.

[64] In 2015, MGH was named the number one hospital in the United States by U.S. News & World Report and is nationally ranked in 16 specialties.

[65] In 2011, MGH was also ranked as one of the top three hospitals in the country for Diabetes & Endocrinology; Ear, Nose & Throat; Neurology & Neurosurgery; Ophthalmology; Orthopedics; and Psychiatry.

This study came after significant pressure on medical practitioners to stop using invasive procedures to try to alter behavior of patients and was denounced as "a new form of lobotomy".

In 2019, MGH paid $13 million and agreed to improve safety practices, to settle Burke's wrongful termination suit.

[70] Also in 2019, MGH paid $5.1 million to settle a medical malpractice lawsuit involving a concurrent surgery performed on former Boston Red Sox baseball team pitcher Bobby Jenks.

[70] Dr. Lisa Wollman refiled her lawsuit in June 2017 under the federal False Claims Act, citing concerns that the hospital was driven by economic benefit and keeping patients unaware of the practice of concurrent surgeries.

Wollman's attorney claimed that Medicare and Medicaid were being defrauded because they require that the surgeons must be present for all "critical portions" of the surgery in order to be compensated.

[71] MGH settled the lawsuit in 2022 for $14.9 million, including reimbursement for the disputed government payments, and agreed to get specific consent for the practice from patients.