Sullivan was born on April 14, 1866, in Feeding Hills, Agawam, Massachusetts. According to her baptismal certificate, her name at birth was Johanna Mansfield Sullivan; however, she was called Anne or Annie from birth. She was the oldest child of Thomas and Alice (Cloesy) Sullivan, who emigrated to the United States from Ireland during the Great Famine.

Due to reports of cruelty to inmates at Tewksbury, including sexually perverted practices and cannibalism, the Massachusetts Board of State Charities launched an investigation into the institution in 1875. The investigation was led by Franklin Benjamin Sanborn, then chairman of the board, and Samuel Gridley Howe, founder of the Perkins School for the Blind in Boston.

In February 1877, Anne was sent to the Soeurs de la Charite hospital in Lowell, Massachusetts, where she had another unsuccessful operation. Remaining there, she helped the nuns in the wards and went on errands in the community until July of that year when she was sent to the city infirmary, where she had one more unsuccessful operation, and was then transferred back to Tewksbury under duress. Instead of returning to the facility for predominantly ill and insane patients, she was housed with single mothers and unmarried pregnant women.

During a subsequent inspection of Tewksbury in 1880 by Franklin Benjamin Sanborn, now State Inspector of Charities, Anne beseeched him to allow her to be admitted to the Perkins School for the Blind. Within months, her plea was granted.

Anne began her studies at the Perkins School on October 7, 1880. Although her rough manners made her first years at Perkins humiliating for her, she managed to connect with a few teachers and made progress with her learning. While there, she befriended and learned the manual alphabet from Laura Bridgman, a graduate of Perkins and the first blind and deaf person to be educated there. Also while there, she had a series of eye operations that significantly improved her vision. In June 1886, she graduated at age 20 as the valedictorian of her class. She stated:

The summer following Sullivan’s graduation, the director of Perkins, Michael Anagnos, was contacted by Arthur Keller, who was in search of a teacher for his seven-year-old blind and deaf daughter, Helen. Anagnos immediately recommended Sullivan for this position, and she began her work on March 3, 1887, at the Kellers’ home in Tuscumbia, Alabama. As soon as she arrived there, she argued with Helen’s parents about the Civil War and over the fact that they used to own slaves. However, she also quickly connected with Helen. It was the beginning of a 49-year relationship: Sullivan evolved from teacher, to governess, and finally to companion and friend.

Sullivan’s curriculum involved a strict schedule with constant introduction of new vocabulary words; however, Sullivan quickly changed her teachings after seeing they did not suit Keller. Instead, she began to teach her vocabulary based on her own interests, by spelling each word out into Keller’s palm; within six months this method proved to be working, as Keller had learned 575 words, some multiplication tables, and the Braille system. Sullivan strongly encouraged Helen’s parents to send her to the Perkins School, where she could have an appropriate education. Once they agreed to this, Sullivan took Keller to Boston in 1888 and stayed with her there. Sullivan continued to teach her bright protégée, who soon became famous for her remarkable progress. With the help of the school’s director Anagnos, Keller became a public symbol for the school, helping to increase its funding and donations and making it the most famous and sought-after school for the blind in the country. However, an accusation of plagiarism against Keller greatly upset Sullivan: she left and never returned, but did remain influential to the school. Sullivan also remained a close companion to Keller and continued to assist in her education, which ultimately included a degree from Radcliffe College.

On May 3, 1905, Sullivan married Harvard University instructor and literary critic John Albert Macy (1877–1932), who had helped Keller with her publications. When she married, Sullivan was already living with Keller as her personal teacher, so Macy moved into the household of both women. However, within a few years, the marriage began to disintegrate. By 1914, they separated, though he is listed as living as a “lodger” with them in the 1920 U.S. Census. As the years progressed after their separation, Macy appears to have faded from her life, and the two never officially divorced. Sullivan never remarried.

In 1932, Keller and Sullivan were each awarded honorary fellowships from the Educational Institute of Scotland. They were also awarded honorary degrees from Temple University. In 1955, Keller was awarded an honorary degree from Harvard University, and in 1956, the director’s cottage at the Perkins School was named the Keller-Macy Cottage.

Sullivan had been seriously visually impaired for almost all of her life, but by 1935, she was completely blind in both eyes. On October 15, 1936, she had a coronary thrombosis, fell into a coma, and died five days later, on October 20, at the age of 70 in the Forest Hills neighborhood of Queens, New York, with Keller holding her hand. Keller described Sullivan’s last month as being very agitated, but during the last week, she was said to return to her normal generous self. Sullivan was cremated and her ashes interred in a memorial at the National Cathedral in Washington, D.C. She was the first woman to be recognized for her achievements in this way. When Keller died in 1968, her ashes were placed next to those of her teacher Sullivan’s.

Sullivan is the main character in The Miracle Worker by William Gibson, originally produced for television in 1957, in which she was portrayed by Teresa Wright. The Miracle Worker then moved to Broadway and later was produced as a 1962 feature film. Both the play and the film featured Anne Bancroft as Sullivan. Patty Duke, who played Keller on Broadway and in the 1962 film, later played Sullivan in a 1979 television remake. Roma Downey portrayed her in the TV movie Monday After the Miracle (1998). Alison Elliott portrayed her in a 2000 television movie. Alison Pill played her on Broadway in the short-lived 2010 revival, with Abigail Breslin as Keller.

In 2003, Sullivan was inducted into the National Women’s Hall of Fame.