The hospital was named after Pierre Simon Vincent Hamot, a successful French businessman who had settled in Erie in the early 19th century and became an active member of the community.

Following his death in 1846, his children and grandchildren donated the Hamot Homestead for use as a general hospital.

The Hamot Homestead facility quickly outgrew its 25 patient capacity, and the first of many expansions was conducted in 1888.

[5] Hamot's marketing campaigns have used a variety of themes, including "...it matters where you go", and "leading the way to better health".

[6] On January 10, 2011, Hamot's board of trustees unanimously approved a formal agreement to affiliate and integrate into UPMC as the medical center's tertiary hub for northwestern Pennsylvania.