Originally named the Yale Scientific School, it was renamed in 1861 in honor of Joseph E. Sheffield, a railroad executive.

After technological developments in the early nineteenth century, such as the electric telegraph, an interest was fostered in teaching applied science at universities.

Classes and labs were hosted in the Second President's House on Yale's Old Campus until funding and a suitable facility could be found.

[2]: 8  The old Yale Medical School building on the northeast corner of Grove and Prospect Streets was renovated and renamed (South) Sheffield Hall.

Yale also received US$591,000 from his will as well as his house, the Sheffield mansion, designed and originally owned by Ithiel Town (demolished in 1957).

Professor Othniel Charles Marsh of the school led four Yale scientific expeditions in search of fossils in 1870-3.

Becton Laboratory (designed by Marcel Breuer, 1970) now stands on the site of North Sheffield and Winchester Halls (demolished in 1967).

Byers Hall, designed by Hiss and Weekes and built in 1903, served as a center for social and religious life.

Also, in 1913, land in East Lyme was purchased for a field engineering camp (now the Yale Outdoor Education Center).

The centennial was celebrated in 1947 with the Silliman lectures given by Ernest O. Lawrence, Linus Pauling, W. M. Stanley and George Wells Beadle.

The Board of Trustees still exists to oversee the Sheffield Scientific School property and meet legal requirements.