It is home to the top-15 ranked Mayo Clinic Alix School of Medicine in addition to many of the highest regarded residency education programs in the United States.

Mayo Clinic is a nonprofit hospital system with campuses in Rochester, Minnesota; Scottsdale and Phoenix, Arizona; and Jacksonville, Florida.

[37]: 32–33  The family relocated within Minnesota several times until Mayo's appointment as an examining surgeon for the Union Army military draft board during the American Civil War brought them to Rochester.

[37]: 78  On January 27, 1864, Mayo advertised in the Rochester City Post the opening of a private medical practice "over the Union Drug Store on Third Street" with "all calls answered by day or night".

Needing nurses, he reached out to Mother Alfred Moes, the founder of the Sisters of Saint Francis of Rochester, Minnesota (a teaching order).

[37]: 244 After the crisis subsided, Mother Alfred approached W. W. Mayo with a proposal: The Sisters of St. Francis would raise funds to build a hospital in Rochester if he and his sons provided medical and surgical care.

[38]: 11–22 The growing specialization of medicine and the expanding use of railroads, automobiles, and mass communications provided context for the development of integrated multi-specialty practice.

[37]: 359  Mayo Clinic's first partners were physicians Augustus W. Stinchfield,[44] Christopher Graham,[45] Melvin C. Millet,[46] Henry Plummer,[47] E. Star Judd,[48] and Donald Balfour.

[43]: 19  A polymath whose interests included architecture, engineering, and art, Plummer also created many of the systems and procedures that remain central to Mayo Clinic today, such as the integrated "dossier" medical record.

[43]: 23–25  In 1919, the brothers and their wives donated the assets of the medical practice including land, buildings, and equipment, as well as the majority of their life savings, to transform the private partnership into a not-for-profit organization.

[59] In November 2019, the Mayo Clinic, in a joint partnership with SEHA Abu Dhabi Health Services Co, invested $50 million into a 741-bed hospital in the United Arab Emirates for a 25% stake.

[15][16] In the early 20th century, Henry Plummer developed Mayo Clinic's multi-specialty group practice model and an integrated medical record system.

[72] During World War II, the U.S. Army tasked Mayo Clinic with finding a solution for dying pilots after suffering blackouts.

Mayo Clinic hired a team of physicians to research and define the specific physiologic effects causing blackout and unconsciousness during high G forces.

[75] Professor Edward C. Kendall, Ph.D., and Philip S. Hench of Mayo Clinic were jointly awarded the Nobel Prize in medicine alongside Tadeus Reichstein, a Swiss chemist who conducted independent research, for the discovery.

[84][85] In 2013, Mayo Clinic specialists in regenerative medicine began the "first-in-human study," whereby patient cells are used to attempt to heal heart damage.

[88] In 2020, Mayo Clinic began running a federally sponsored Expanded Access Program for Convalescent Plasma to treat hospitalized patients with COVID-19 in the United States.

[89] In 2018, Mayo Clinic and UCLA used spinal cord stimulation and physical therapy that allowed a man paralyzed since 2013 to briefly regain his ability to stand and walk with assistance.

Rochester business leader John Kahler built innovative hotel-hospital facilities that served Mayo Clinic patients.

[37]: 544 [43]: 38–41  This approach was replicated and enhanced with the adjoining 1928 Mayo Clinic building, later named for Plummer,[43]: 77–80  its principal designer, which is listed on the National Register of Historic Places.

The doors are closed to memorialize important historical events and influential people, such as the deaths of the Mayo brothers, the assassination of President John F. Kennedy, and the victims of the September 11, 2001, terrorist attacks.

[36][100] MFMER was established as a department of the University of Minnesota with a $1.5 million donation to offer graduate programs at the Mayo Clinic in Rochester.

[38]: 131 In 2011, the foundation that oversees the Mayo Clinic went before the Supreme Court to argue that medical residents should remain exempt from Social Security deductions.

In Mayo Foundation v. United States, the court sided with the Social Security Administration and required FICA to be deducted going forward.

[28] Under his leadership, Mayo Clinic was reorganized into a single operating company with a unified strategy and business plan, which helped the system expand.

[116] Minnesota state senator Erin Murphy called Mayo's efforts to gut the bill "corporate hijacking" in an op-ed published in the Star Tribune.

More apps were created for Mayo Clinic Care Network members to help patients see their medical records or ask clinicians for assistance.

[118] In 2014, Mayo Clinic was developing an app for Apple's HealthKit to help users maintain healthy lifestyles and warn of certain health signs that need attention.

[120] In March 2018, Mayo Clinic and Mytonomy, a healthcare education system company, partnered to provide video content for cancer patients.

[122] In January 2020, Mayo Clinic and NTT Venture Capital joined a $60 million financing for biomedical software startup inference.