Homer qualified as a lawyer in 1980 whilst at Reading Borough Council. In 1982, she joined Hertfordshire County Council where she stayed for 15 years, rising to director of corporate services. She then left to join Suffolk County Council as chief executive in 1998. After four years at Suffolk, Homer went on to be the chief executive of Birmingham City Council in 2002 and joined the civil service in 2005. In 2005, Homer was criticised by the Election Commissioner for failings in her role as returning officer during a postal vote-rigging scandal involving Labour candidates the previous year, described by the Commissioner as one that "would disgrace a banana republic", and involving hundreds of votes failing to be counted. Homer defended her role to the Election Commission, saying she had been in "strategic, not operational control", and had confined herself to "motivational management and fire fighting".
Homer resigned from her post shortly afterwards, joining the civil service as the Director-General heading the Immigration and Nationality Directorate of the Home Office, in August 2005. The Home Office was re-organised in 2008, with the formation of the Border and Immigration Agency, later renamed the UK Border Agency, of which Homer became the first chief executive. In 2013, Homer's tenure at UKBA was criticised for its "catastrophic leadership failure" by the House of Commons Home Affairs Select Committee, which said it had been repeatedly misled by the Agency. Committee chairman Keith Vaz said her performance was "more like the scene of a Whitehall farce than a government agency operating in the 21st century". Homer responded in a letter to the committee, saying that "The suggestion that I deliberately misled the Committee and refused to apologise are both untrue and unfair," adding that "It is therefore wholly inaccurate and unfair to seek to ascribe responsibility to me for matters of concern that occurred long after I left the Agency."
In 2010 it was announced that Homer would replace Robert Devereux as Permanent Secretary of the Department for Transport. While serving in this role, the DfT oversaw with the controversial franchise letting process for the InterCity West Coast rail franchise that had to be cancelled after significant technical flaws were later discovered in awarding the franchise to FirstGroup. Homer was among officials accused by Richard Branson, head of the Virgin Rail Group, of ignoring concerns about the letting process, whose failure is estimated to have cost £100 million.
In December 2011 it was announced that Homer would succeed Lesley Strathie as Chief Executive of HM Revenue and Customs. Homer's appointment to head of HMRC prompted criticism centred on her record in previous positions. However, her appointment was supported by David Gauke, the Exchequer Secretary to the UK Treasury, who said: "She is a highly effective chief executive and the right person to lead HMRC." In March 2013, HMRC was criticised by the House of Commons Public Accounts Select Committee for its "unambitious and woefully inadequate" response to a report from the UK National Audit Office in December 2012 concerning poor customer service by HMRC. Homer said the agency had "turned a corner" in dealing with the 79 million calls and 25 million pieces of post received by HMRC each year, having injected £34 million to tackle the problem with that aim of reaching a 90 per cent success rate. As of 2015, Homer was paid a salary of between £185,000 and £189,999 by the department, making her one of the 328 most highly paid people in the British public sector at that time. On 11 January 2016, Homer announced she would retire from her post as chief executive of HMRC in April of that year. Reviewing her performance following another summons by the Public Accounts Committee, just before retirement, she was nicknamed "Dame Disaster" by the Guardian's John Crace. She was succeeded by Jon Thompson.
