Born in Cincinnati, Ohio, Nellie was the fourth of eleven children of Judge John Williamson Herron (1827–1912), a college classmate with Benjamin Harrison and a law partner of Rutherford B. Hayes. Her mother, Harriet Collins Herron (1833–1902), was the daughter and the sister of U.S. congressmen; Nellie's grandfather, Ela Collins, and uncle, william Collins, were both members of Congress. During her childhood she was called Nelli rather than Helen; she was referred to as such in the family since her only daughter was named Helene. Nellie Herron was enrolled in private Miss Nourse School, known in Cincinnati as The Nursery, in 1866-1879, and took classes from the University of Cincinnati. Starting from 1882, she taught in different schools until her marriage. In 1877, she attended with her parents the twenty-fifth wedding anniversary celebration of President and Mrs. Rutherford B. Hayes and stayed for a week at the White House.

In 1879, she met william Howard Taft at a bobsledding party in Cincinnati; he was 22 years old, she was 18. He asked her out for the first time in February 1880, but they did not go out regularly until 1882. He proposed in April 1885, and she accepted in May.

Taft married Nellie on June 19, 1886, at the home of the bride's parents in Cincinnati. The wedding was performed by the Reverend D.N.A. Hoge of Zanesville, Ohio. Taft's younger brother Horace Taft was best man. The couple honeymooned one day in New York City and four days at Sea Bright, New Jersey, before setting off on a three-month tour of Europe.

The Tafts had two sons and a daughter. Robert A. Taft (1889–1953) was a Politician and statesman, Helen Taft Manning (1891–1987) was an educator, and Charles Phelps Taft II (1897–1983) was a civic leader.

On their return, they settled in Cincinnati. Nellie Taft encouraged her husband's political career despite his often-stated preference for the judiciary. However, she welcomed each step in his judicial career: state judge, Solicitor General of the United States, and federal circuit court judge. In 1900, Taft agreed to take charge of American civil government in the Philippines as Governor-General (1900-1903). Nellie Taft moved with their children to Manila where she tried to reconcile with the local population by showing respect to the culture of the Philippines by learning the language, wearing a native Filipino costume and inviting Filipinos to social events. Further travel with her husband, who became Secretary of War in 1904, brought a widened interest in world politics and a cosmopolitan circle of friends.

In May 1909, Nellie Taft suffered a stroke, impairing her speech, right arm and leg. The stroke happened at the beginning of her husband's presidential term. Assisted by her four sisters, she continued her functions as White House host until she recovered with the help of her husband.

The social highlight of the Taft administration was the Tafts' silver wedding anniversary gala on June 19, 1911 for some 2,000 guests.

In June 1912, she attended both the Republican National Convention that re-nominated her husband and the Democratic National Convention that nominated his opponent Woodrow Wilson. She took a front-row seat at the latter in order to deter speakers' criticism of her husband. After losing the election, the Tafts returned to Cincinnati, where william began teaching law. Nellie Taft wrote her memoir, Recollections of Full Years, which was published in 1914. During the Great War, she provided support for the American Red Cross.

With Taft's appointment to the Supreme Court in 1921, Nellie Taft became the only woman to be both First Lady and wife of a chief justice. She resumed her social activities after returning to Washington D.C.

Nellie Taft was widowed upon the death of her husband on March 8, 1930, and stayed in the city of Washington. She continued to be socially involved serving as an honorary vice President of the Colonial Dames of America and the Girl Scouts of America. She died in Washington, D.C. on May 22, 1943, and was buried next to the President at Arlington National Cemetery which created a precedent later used for Jacqueline Kennedy.

Nellie Taft was the first First Lady to ride in her husband’s inauguration parade, which she did despite adverse weather. She started to receive guests three afternoons a week in the Red Room. At times, she attended the cabinet meetings with the President without speaking on the issues. She introduced musical entertainment after state dinners which became a White House tradition. The Tafts attended symphony, opera, and theater performances in Washington D.C.; she started another summer tradition at West Potomac Park with the United States Marine Band playing for the public.