She first came into public prominence while serving as deputy White House Counsel for President Bill Clinton, whom she defended during his 1999 impeachment trial.

[16] Her presentation to the Senate focused on refuting the obstruction of justice charge and the House Managers' claim that failure to convict the President would damage the rule of law.

[17] While at NYU, she played a central role in the university administration's efforts around union contracts with adjunct faculty[18][19] and graduate students.

[20][21] The Washington Post reported in October 2015 that, during Mills' first four months at the State Department, she continued to work at NYU on a part-time basis, negotiating with officials in Abu Dhabi to build a campus in the United Arab Emirates city.

[22] She worked for no pay in those first months at the State Department, and was officially designated as a "temporary expert-consultant", which allowed her to continue receiving outside income while serving as Clinton's Chief of Staff.

Several months after her appointment, former White House Press Secretary Joe Lockhart noted in an interview: “I think Secretary Clinton wants to know you’re a team player, but she wants to hear it straight and she gets exactly that from Cheryl.”[24] In summer 2016, CNN reported on another ethical question pertaining to Mills' relationship with the Clinton Foundation during her tenure at the State Department: In 2012 Mills had traveled to New York City in order to assist the foundation by conducting interviews in a high-level candidate search.

[25] Mills' attorney emphasized that she had assisted on a strictly volunteer basis, and was not paid for her services or travel; a State Department spokesperson indicated that such an undertaking was not in conflict with federal ethics rules.

[28] In 2002, the United States Court of Appeals for the Seventh Circuit reiterated that government lawyers may not exercise an attorney-client privilege in an effort to shield information from a grand jury.

Senators posed questions regarding Miss Mills and her colleague Heather Samuelson within the unprecedented relationships between her government duties and her private practice in light of possible scenario of obstruction of justice to Michael Horowitz and Christopher Wray.

[31] Mills oversaw the department's interagency global hunger and food security initiative (Feed the Future) and diplomacy and development efforts in Haiti working closely with USAID and others across the government.

Shortly after taking office Secretary Clinton asked Mills to lead an interagency consultation of current agriculture and food security efforts.

"[35] In her keynote speech at the ribbon-cutting ceremony at Caracol Industrial Park on October 22, 2012, then-Secretary of State Hillary Clinton praised Mills as "a real driver of our government’s support for everything that we see here today".

In 1990, she worked with DCWorks, a non-profit organization that supported the academic and social development of underprivileged high school students of color.

"[40] On March 26, 2014, Elle magazine honored Mills at the Italian Embassy in the United States during its annual “Women in Washington Power List” celebration.