Safford was born in Hyde Park, Vt. and lived in Crete, Ill., from age 3. in 1849, following her parents' death, family members secured her education at an academy in Bakersfield, Vt., then allowed her to travel in Canada to learn French and act as governess to a German-speaking family to acquire skill in German. Unmarried, she took up residence with her elder brother Alfred Safford, a Joliet, Ill., businessman, then moved with him to Shawneetown, and in 1858 to Cairo, Ill. Safford's exact birthdate is unknown, but she is thought to have been 29 at the outbreak of the Civil War.

On the arrival of nurse Mary Ann "Mother" Bickerdyke in Cairo in summer 1861, Safford volunteered to work with her as a nursing aide, showed talent, and was pressed into full-time nursing. With Bickerdyke, she cared for troops succumbing to camp diseases and the large numbers of wounded from the Battles of Belmont and Fort Donelson. Though based at the large field hospital in Cairo, she often left the facilities to care for the sick in surrounding camps, and is remembered for walking the Belmont battlefield under her own flag of truce searching out the wounded. After the Battle of Fort Donelson, Bickerdyke recalled that Safford worked 10 days in the Cairo hospital with little sleep, neared collapse, then accepted nursing duties aboard the transport boat City of Memphis. These exertions forced her to retire to her brother's home in poor health.

Safford returned to nursing for the Battle of Shiloh, working aboard the transport boat Hazel Dell and with Bickerdyke in Savannah, Tenn., field hospitals. An attractive, polished, compassionate woman, she impressed her patients aboard the Hazel Dell and won the sobriquet "Angel of Cairo." However, overworked and weak, she suffered a breakdown after caring for the Shiloh wounded, was confined to bed for several months, then, at her brother's urging, accompanied the family of former Illinois governor Joel Matteson on a lengthy European tour to recuperate. She did not return to the U.S. until autumn 1866.

Interested in resuming medical work, Safford entered the New York Medical College for Women in 1867; graduated in 1869; studied surgery at the General Hospital of Vienna, Austria, through 1 871; continued studies at the University of Breslau, Germany, for several months, performing there the first ovariotomy ever done by a woman; returned to the U.S. late in 1872; and in 1873 opened a private practice in Chicago. In 1872 she married James Blake. When the marriage proved unworkable, Safford joined the Boston University School of Medicine faculty, divorced Blake in 1880, then retired from the school in poor health in 1886. She took up residence in Tarpon Springs, Fla., where she died in 1891.