The Independent Order of St. Luke was founded in Baltimore in 1867. When the order moved into Richmond, it did not flourish as other societies had. In 1899, when Walker was elected secretary, it was on the verge of bankruptcy. She brought some training in business, 16 years of experience holding minor posts in the order, and energy, enthusiasm, and organizational ability to the job. St. Luke soon created the combined position of secretary-treasurer for her, and she devoted the rest of her life to building membership and resources, expanding activities in business and social service, and keeping the financial base efficient. She liked to describe the order as a woman's organization that gave equal opportunity to men. At its height in the 1920s it claimed 100,000 members in 22 states.

In addition to real estate and the insurance program, the major St. Luke businesses founded under Walker's leadership included the St. Luke Penny Savings Bank, which opened in 1903. It had a woman president and several women board members. By 1931 it had merged with the two remaining African American banks in Richmond, resulting in the Consolidated Bank and Trust Company, which still existed in the mid-1980s. Walker is often described as the first woman bank president in the United States, but her achievement lay in presiding over a successful bank. Another project, the order's newspaper, the St. Luke Herald, printed outspoken editorials on the condition of African Americans in bigoted times.

As segregation in the South increased, many African American leaders emphasized entrepreneurship, "buy Black" campaigns, and the employment of African Americans as a primary avenue for community advancement. Walker agreed to that agenda and added a powerful plea for the creation of employment for African American women other than in domestic service.

Walker was a charismatic speaker whose favorite topics were race pride and unity, women's problems and potential, African American business, and oppression. As her importance grew, she became more and more active in civic affairs. She was the founder and lifelong head of the Colored Women's Council of Richmond, which raised money for local projects and maintained a community house.

She served many years on the executive committee of the National Association of Colored Women, whose projects included restoring and opening the Frederick Douglass Home to the public. For over a decade she was a member of the board of the National Association for the Advancement of Colored People and the guiding spirit of the Richmond branch. She was on the board of the Richmond Urban League and a member of the Interracial Commission. She was on the board of two schools for girls—one in Richmond and one in Washington—and served as a trustee of Hartshorn College and Virginia Union University. She was an active contributor to the work of her beloved First African Baptist Church.

Walker became a relatively wealthy woman and a philanthropist. Her home was made a national historic site, administered by the National Park Service. There one can see how the family lived, learn about the Richmond African American community, and appreciate the breadth of her friendships. The library walls are lined with pictures of friends: Booker T. Washington, W. E. B. DuBois, Marcus Garvey, Nannie Helen Burroughs, Mary McLeod Bethune, Langston Hughes, and many others. The shelves are full of books on African American history and life.

Walker achieved what she did despite the heavy social odds against her. She also had personal handicaps and suffering. In 1915 her husband Armstead was shot and killed by their son, Russell, who mistook his father for a burglar. He was indicted for murder, but acquitted. Walker had severe health problems and spent the last seven years of her life in a wheelchair. However, she continued to travel to places as far away as Florida and Chicago. Walker died of diabetic gangrene on December 15, 1934. According to tradition, her last message was "Have hope, have faith, have courage, and carry on."