Seelye taught at Amherst from 1865 until his election as President of the newly formed Smith College in nearby Northampton, Massachusetts in 1873.

They had seven children: Ralph Holland, Harriet Chapin (who would marry Benjamin Rush Rhees)[2] Abigail Taylor, Arthur, Walter Clark, Henrietta, and Bertram.

A measure of his success, and of the changing times, may be seen in the fact that, when he retired, the Smith College enrollment had grown from 14 to 1635, and the number of faculty had increased from 4 to 105.

He was a member of the first board of superintendents of the Smith Agricultural School, and when the Red Cross formed a chapter in Northampton he was its first president.

As President Emeritus, he was active in the social and ceremonial life of Smith College, and was a fixture at the annual Commencement exercises.