By the time Lewis reached the age of nine, both of her parents had died; Samuel Lewis died in 1847 and Robert Benjamin Lewis in 1853. Her two maternal aunts adopted her and her older half-brother Samuel. Samuel was born in 1835 to his father of the same name, and his first wife, in Haiti. The family came to the United States when Samuel was a young child. Samuel became a barber at age 12 after their father died.

The children lived with their aunts near Niagara Falls, New York, for about four years. Lewis and her aunts sold Ojibwe baskets and other items, such as moccasins and embroidered blouses, to tourists visiting Niagara Falls, Toronto, and Buffalo. During this time, Lewis went by her Native American name, Wildfire, while her brother was called Sunshine. In 1852, Samuel left for San Francisco, California, leaving Lewis in the care of a Captain S. R. Mills. Samuel provided for her board and education.

In 1856, Lewis enrolled in a pre-college program at New-York Central College, McGrawville, a Baptist abolitionist school. At McGrawville, Lewis met many of the leading activists who would become mentors, patrons, and possible subjects for her work as her artistic career developed. In a later interview, Lewis said that she left the school after three years, having been “declared to be wild.”

In 1859, when Edmonia Lewis was about 15 years old, her brother Samuel and abolitionists sent her to Oberlin, Ohio, where she attended the secondary Oberlin Academy Preparatory School for the full, three-year course, before entering Oberlin Collegiate Institute (since 1866, Oberlin College), one of the first U.S. higher-learning institutions to admit women and people of differing ethnicities. The Ladies’ Department was designed “to give Young Ladies facilities for the thorough mental discipline, and the special training which will qualify them for teaching and other duties of their sphere.” She changed her name to Mary Edmonia Lewis and began to study art. Lewis boarded with Reverend John Keep and his wife from 1859 until she was forced from the college in 1863. At Oberlin, with a student population of one thousand, Lewis was one of only thirty students of color. Reverend Keep was white, a member of the board of trustees, an avid abolitionist, and a spokesperson for coeducation.

Lewis was inspired by the lives of abolitionists and Civil War heroes. Her subjects in 1863 and 1864 included some of the most famous abolitionists of her day: John Brown and Colonel Robert Gould Shaw. When she met Union Colonel Robert Gould Shaw, the commander of an African-American Civil War regiment from Massachusetts, she was inspired to create a bust of his likeness, which impressed the Shaw family, who purchased her homage. Lewis then made plaster cast reproductions of the bust; she sold one hundred at 15 dollars apiece. This was the most famous work to date and the money she earned from the busts allowed her to eventually move to Rome. Anna Quincy Waterston, a poet, then wrote a poem about both Lewis and Shaw.

After college, Lewis moved to Boston in early 1864, where she began to pursue her career as a sculptor. She repeatedly told a story about encountering in Boston a statue of Benjamin Franklin, not knowing what it was or what to call it, but concluding she could make a “stone man” herself. This cannot possibly be correct: after 2+ years at both Central College and at Oberlin she certainly knew what a sculpture was.

Brackett specialized in marble portrait busts. His clients were some of the most important abolitionists of the day, including Henry Wadsworth Longfellow, Wm. Lloyd Garrison, Charles Sumner, and John Brown. To instruct her, he lent her fragments of sculptures to copy in clay, which he critiqued. Under his tutelage, she crafted her own sculpting tools and sold her first piece, a sculpture of a woman’s hand, for $8. Anne Whitney, a fellow sculptor and friend of Lewis’, wrote in an 1864 letter to her sister that Lewis’s relationship with her instructor did not end amicably, but did not disclose the reason for the split. Lewis opened her studio to the public in her first solo exhibition in 1864.

From 1864 to 1871, Lewis was written about or interviewed by Lydia Maria Child, Elizabeth Peabody, Anna Quincy Waterston, and Laura Curtis Bullard: all important women in Boston and New York abolitionist circles. Because of these women, articles about Lewis appeared in important abolitionist journals, including Broken Fetter, the Christian Register, and the Independent, as well as many others. Lewis was aware of her reception in Boston. She was not opposed to the coverage she received in the abolitionist press, and she was not known to turn down monetary aid, but she could not tolerate the false praise. She knew that some did not really appreciate her art, but saw her as an opportunity to express and show their support for human rights.

The success and popularity of these works in Boston allowed Lewis to bear the cost of a trip to Rome in 1866. On her 1865 passport is written, “M. Edmonia Lewis is a Black girl sent by subscription to Italy having displayed great talents as a sculptor”. The established sculptor Hiram Powers gave her space to work in his studio. She entered a circle of expatriate artists and established her own space within the former studio of 18th-century Italian sculptor Antonio Canova. She received professional support from both Charlotte Cushman, a Boston actress and a pivotal figure for expatriate sculptors in Rome, and Maria Weston Chapman, a dedicated worker for the anti-slavery cause.

Her half-brother Samuel became a barber in San Francisco, eventually moving to mining camps in Idaho and Montana. In 1868, he settled in the city of Bozeman, Montana, where he set up a barber shop on Main Street. He prospered, eventually investing in commercial real estate, and subsequently built his own home which still stands at 308 South Bozeman Avenue. In 1999 the Samuel Lewis House was placed on the National Register of Historic Places. In 1884, he married Mrs. Melissa Railey Bruce, a widow with six children. The couple had one son, Samuel E. Lewis (1886–1914), who married but died childless. The elder Lewis died after “a short illness” in 1896 and is buried in Sunset Hills Cemetery in Bozeman. The mayor of Bozeman was a pallbearer.

Her work sold for large sums of money. In 1873 an article in the New Orleans Picayune stated: “Edmonia Lewis had snared two 50,000-dollar commissions.” Her new-found popularity made her studio a tourist destination. Lewis had many major exhibitions during her rise to fame, including one in Chicago, Illinois, in 1870, and in Rome in 1871.

Lewis never married and had no known children. According to her biographer, Dr. Marilyn Richardson, there is no definite information about her romantic involvement with anyone, male or female. However, in 1873 her engagement was announced, and in 1875, still engaged, his skin color was revealed to be the same as hers, although his name is not given. There is no further reference to this engagement, which could well be another of Lewis’ “white lies”.

A major coup in her career was participating in the 1876 Centennial Exposition in Philadelphia. For this, she created a monumental 3,015-pound marble sculpture, The Death of Cleopatra; portraying the queen in the throes of death. This piece depicts the moment popularized by Shakespeare in Antony and Cleopatra, in which Cleopatra had allowed herself to be bitten by a poisonous asp following the loss of her crown. Of the piece, J. S. Ingraham wrote that Cleopatra was “the most remarkable piece of sculpture in the American section” of the Exposition. Much of the viewing public was shocked by Lewis’s frank portrayal of death, but the statue drew thousands of viewers nonetheless. Cleopatra was considered a woman of both sensuous beauty and demonic power, and her self-annihilation has been portrayed numerously in art, literature and cinema. In Death of Cleopatra, Edmonia Lewis added an innovative flair by portraying the Egyptian queen in a disheveled, inelegant manner, a departure from the refined, composed Victorian approach of representing death. Considering Lewis’s interest in emancipation imagery as seen in her work Forever Free, it is not surprising that Lewis eliminated Cleopatra’s usual companion figures of loyal slaves from her work. Lewis’s The Death of Cleopatra may have been a response to the culture of the Centennial Exposition, which celebrated one-hundred years of the United States being built around the principles of liberty and freedom, a celebration of unity despite centuries of slavery, the recent Civil War, and the failing attempts and efforts of Reconstruction. In order to avoid any acknowledgement of black empowerment by the Centennial, Lewis’s sculpture could not have directly addressed the subject of Emancipation. Although her white contemporaries were also sculpting Cleopatra and other comparable subject matter (such as Harriet Hosmer’s Zenobia), Lewis was more prone to scrutiny on the premise of race and gender due to the fact that she, like Cleopatra, was female:

A testament to Lewis’s renown as an artist came in 1877, when former US President Ulysses S. Grant commissioned her to do his portrait. He sat for her as a model and was pleased with her finished piece. She also contributed a bust of Charles Sumner to the 1895 Atlanta Exposition.

Lewis lived in the Hammersmith area of London, England, before her death on September 17, 1907, in the Hammersmith Borough Infirmary. According to her death certificate, the cause of her death was chronic Bright’s disease. She is buried in St. Mary’s Roman Catholic Cemetery, in London.

There were earlier theories that Lewis died in Rome in 1907 or, alternatively, that she had died in Marin County, California, and was buried in an unmarked grave in San Francisco.

Later, Marilyn Richardson, an assistant professor in the erstwhile The Writing Program at the Massachusetts Institute of Technology (MIT), and later curator and scholar of African-American art, went searching for The Death of Cleopatra for her biography of Lewis. Richardson was directed to the Forest Park Historical Society and Dr. Orland by the Metropolitan Museum of Art who had earlier been contacted by the historical society regarding the sculpture. Richardson, after confirming the sculpture’s location, contacted African-American bibliographer Dorothy Porter Wesley and the two gained the attention of NMAA’s George Gurney. According to Gurney, Curator Emeritus at the Smithsonian American Art Museum, the sculpture was in a race track in Forest Park, Illinois, during World War II. Finally, the sculpture came under the purview of the Forest Park Historical Society, who donated it to Smithsonian American Art Museum in 1994. Chicago-based Andrezej Dajnowski, in conjunction with the Smithsonian, spent $30,000 to restore it to its near-original state. The repairs were extensive, including the nose, sandals, hands, chin, and extensive “sugaring” (disintegration.)

In 2017, a GoFundMe by East Greenbush, New York, Town Historian Bobbie Reno was successful, and Edmonia Lewis’s grave was restored. The work was done by the E M Lander Co. in London.