In 1999, she became Parliamentary Private Secretary to Peter Hain in his capacity as Minister of State at the Department of Trade and Industry and the Foreign and Commonwealth Office before in 2002 becoming Parliamentary Private Secretary to Dr John Reid, in his capacity as Leader of the House of Commons and Minister without Portfolio.

She joined the Government in June 2003 as Parliamentary Under Secretary of State at the Home Office, before moving in May 2005 to the Department of Health, with responsibility for Public Health first as Parliamentary Under-Secretary of State and from May 2006 as Minister of State in the same role.

As Public Health minister she was responsible for managing government programmes concerning radiation exposure, the potential bird flu epidemic, sex education, and the prevention of communicable diseases such as TB and HIV, and oversaw campaigns to tackle obesity, type 2 diabetes, heart disease, and cancer. She was also due to take charge of the enforcement of the Labour government's ban on smoking in all public places, but was moved just a couple of days before it came into force.

In February 2007, it was announced that she would be Hazel Blears' campaign manager in Blears' campaign for the Deputy Leadership election of the Labour Party following John Prescott's resignation. Blears was did not win, finishing sixth in the Deputy Leadership election, but her conduct during the campaign was rewarded with the Cabinet Post of Secretary of State for Communities and Local Government.

In the cabinet reshuffle of 29 June 2007 Caroline Flint moved to the Department for Work and Pensions where she served as the Minister for Employment and Welfare Reform. Flint was also appointed to the new position of Minister for Yorkshire and the Humber. On 24 January 2008, Flint was promoted to Minister of State for Housing and Planning, and as a result will now attend cabinet. She relinquished her role as regional minister.

In May 2008 she inadvertently revealed her grim forecast for the future of house prices when she was photographed walking into Downing Street with her briefing papers visible. Close inspection revealed that her document read: "We can't tell how bad it will get."