Dr. William Worrall Mayo was born in England and traveled to America in 1845. He practiced as a chemist in New York and later served as a chemistry and physics instructor at the Bellevue Hospital Medical College. He completed his medical studies in 1854 at the University of Missouri, then traveled to Minnesota where he served as the first county commissioner of St. Louis County before relocating to Le Seuer.
Dr. Mayo hand-built his Gothic-style home in 1859 and set up his first medical practice in a small room upstairs. He and his family lived in the house at the time of the U.S.-Dakota War of 1862. In August 1862, Dr. Mayo volunteered to go to the relief of besieged New Ulm, where he helped care for the wounded. His wife, Louise, remained in Le Seuer and opened her home and barn to 11 refugee families. In December 1862, after 38 Dakota men were hanged in Mankato and their bodies were buried in shallow graves nearby, doctors in the area, including Dr. Mayo, unearthed some of the bodies for medical study and demonstrations. Dr. Mayo gained possession of the body of Cut Nose, a Dakota warrior, which became an object of careful study for the younger Mayos.
In 1864, Dr. Mayo moved his family to Rochester, where he served as an examining surgeon for the Minnesota Civil War draft board. During the 1880s, Dr. Mayo's two sons William and Charles, joined his practice, and St. Mary's hospital was built with the Mayos as supervising physicians. Soon other non-family members joined the practice, introducing the concept of medical teamwork, and by the early 20th century, the hospital had become known as the "Mayos’ Clinic."
Carson Nesbit Cosgrove and his family moved into the Mayo House in 1874. By coincidence, his wife was also named Louise. Three generations of the Cosgrove family lived in the home through 1920. In 1903, Cosgrove conducted the organizational meeting and later served as the head of the Minnesota Valley Canning Company, which became the Green Giant Company in 1950. Seven children from the second and third generations of the family were born in the home including two Green Giant Company presidents.