An influential figure in the development of the Unitarian Universalist church in the Midwestern United States, she was a member of the informally-designated group of religious figures known as the "Iowa Sisterhood", as was her childhood friend Eleanor Gordon.

[2] She began preaching as a child on the family farm, standing on a tree stump to deliver her sermons.

She studied for a year at the University of Iowa before leaving due to illness, both hers and that of her older sister; returning to Illinois, she took a position as a teacher.

[1] In 1871 she and Gordon founded the Hawthorne Literary Society; in 1880, the two women were ordained and took over leadership of the Christian Unity Church in Humboldt, Iowa.

Safford retired to Florida in 1910, helping to found the Unitarian Church in Orlando until her death,[2] which was likely precipitated by a fall which broke her hip, after which she used a wheelchair.