Williams was an aide to Representative Morris K. Udall, Democrat of Arizona from 1977–78, Press Secretary for the Democratic National Committee in 1979, manager of the Press office of the D.N.C. convention in 1980, campaign press secretary for Representative Robert G. Torricelli, Democrat of New Jersey in 1982. She was director of media relations for the Center on Budget and Policy Priorities in 1983, a member of the convention staff of the D.N.C. in 1984 and communications director for the Children's Defense Fund, 1984-1990.
While at the Children's Defense Fund she met, and became friends with then First Lady of Arkansas Hillary Clinton. She served as Clinton's transition director in 1992 and as her chief of staff during her first term as First Lady of the United States, the first African American woman to hold that position and the first Chief of Staff to the First Lady who also served as an Assistant to the President. As stated in Taylor Branch's , in 1994, President Clinton turned to Williams "to compile confidential suggestions" on personnel shifts... According to Branch, "When I asked how unusual it was for the first lady's office to be involved, he replied there was no easy blueprint for reorganizing the organizers. Williams was shrewd, discreet, and efficient." In a profile in Essence Magazine Ana Perez, who during George Bush's administration was the first Black person to serve as a press secretary to a First Lady said of Williams: "I am in awe of her...I have so much respect for her because she has this absolutely calm center and because she is a good and decent person. She's a do-gooder in every sense of the word." She has been described as having "very good judgment on issues and people" by Leon Panetta.
On the night of the death of deputy White House counsel Vince Foster in 1993, a Secret Service agent claimed he saw Williams remove two handfuls of folders from his office, which she vehemently denied.
Williams became the campaign manager for Hillary Clinton's 2008 presidential campaign after being brought on as a senior adviser following Clinton's win in the New Hampshire primary in January 2008. On February 10, 2008, she replaced Patti Solis Doyle as the campaign's manager. and infused Clinton's campaign "with a sense of purpose" according to staffers. In this capacity she defended the Clinton campaign's decision to circulate pictures of rival candidate Barack Obama wearing traditional Somali clothing, stating, "If Barack Obama's campaign wants to suggest that a photo of him wearing traditional Somali clothing is divisive, they should be ashamed." In their book, The Battle for America: The Story of an Extraordinary Election, Haynes Johnson and Dan Balz wrote that with Williams in charge the campaign was more collegial and operated with greater efficiency.