Eggleton, an accountant by profession, was first elected to Toronto city council in 1969. He served as budget chief in the council elected in 1973 under David Crombie. He was the Liberal Party of Canada's candidate in the October 16, 1978 federal by-election held in Toronto's west-end Parkdale electoral district. He was defeated by Progressive Conservative candidate Yuri Shymko. He then ran for Toronto City Council in Ward 4. On November 13, 1978, he finished first amongst a field of 10 candidates and became Ward 4's senior alderman on council (at the time, two alderman were elected from each ward).
Eggleton served the city of Toronto as a member of Toronto City Council and the Metropolitan Toronto Council for 22 years. He was Mayor of Toronto from 1980 until 1991, when he retired from municipal politics as the longest-serving mayor in Toronto history.
In 1980, he was elected Mayor of Toronto after defeating incumbent John Sewell. During Eggleton's time as Mayor, the City moved forward on implementing its new official plan which resulted in several new significant buildings in the downtown west, or railway lands area - the Convention Centre, Skydome, and the CBC Broadcast Centre, to name a few. The City administration under his leadership also produced a record level of social housing projects for low income people; 50 acres (20 ha) of new parks; innovative new responses to the problems of the homeless and emotionally troubled with projects like Street City, the Singles Housing Opportunities Program, and the Gernsteins Centre. He established the Mayor's Committee on Community and Race Relations to help bring about the successful integration of people from different cultural, racial, and ethnic backgrounds. At the same time, however, Eggleton continually refused to acknowledge the city's gay and lesbian community by declining to officially recognize Toronto's Lesbian and Gay Pride Parade each June. As mayor he supported human rights including gay rights though at the time did not see the parade as the usual kind of event for a mayor's declaration. Eggleton has attended the parade several times as a member of federal government. In 2011, Eggleton's expressed support for the Pride Parade, urging then Mayor Rob Ford to attend Eggleton was finally outvoted by his fellow council members in 1991, his last year in office. In 1985, he withstood a challenge from city councillor Anne Johnston, a fellow Liberal, who ran against Eggleton for the mayoralty in that year's civic election. In recognition of his service to the City, Mr. Eggleton received Toronto's highest honour, the Civic Award of Merit in 1992.
Eggleton ran in the 1993 election in the suburban Toronto riding of York Centre, again as a Liberal, and won election. He was appointed to the position of President of the Treasury Board and Minister for Infrastructure in the new cabinet.
From January 1996 to June 1997, he served as Minister for International Trade. Eggleton retained his seat in the 1997 election, and was appointed Minister of National Defence. In 1999, Eggleton supported Canada's involvement in NATO's campaign in Kosovo.
He was re-elected again in the 2000 election, and continued as Minister of Defence, focusing on sweeping changes to the National Defence Act which implemented changes to the military justice system, including the set up of several oversight entities including a Military Ombudsman and a Military Police Complaints Commission. He also improved compensation and benefits for Canadian Forces personnel and their families. In January 2002, Chrétien and Eggleton were accused of misleading Parliament. Both Chrétien and Eggleton when asked in Question Period if Canadian troops had handed over captured Taliban and al-Qaeda members in Afghanistan to the American forces amid concerns about the treatment of POWs at Guantanamo Bay, replied that was in Chrétien's words only a "hypothetical question" and that the Canadians had taken no POWs. Critics of the government such as Joe Clark then proceeded to point out that in the previous week, the Toronto newspaper the Globe & Mail had run on its frontpage a photo of Canadian soldiers turning over POWs to American troops. Eggleton maintained that he and the rest of the Cabinet had been kept unaware that the Canadian Forces were taking POWs in Afghanistan and turning them over to the Americans, claiming that he had only learned of the policy of handing over POWs several days after the photo had appeared in the Globe & Mail.
Eggleton resigned from the cabinet in May 2002, amid allegations he hired a former girlfriend for a research contract. The ethics commissioner, Howard Wilson, concluded Eggleton breached conflict guidelines for cabinet ministers, and Eggleton voluntarily stepped down. This happened during the growing leadership turmoil between Prime Minister Jean Chrétien and Paul Martin, who left the cabinet the following week in disputed circumstances. Increased scrutiny on Chrétien's government and cabinet may have contributed to Prime Minister Jean Chrétien pressuring him to resign.
Eggleton then became a member of the Standing Committee on Foreign Affairs and Trade. On May 13, 2004, Eggleton announced he would not be a candidate in the 2004 federal election, making way for the nomination of Ken Dryden as the Liberal candidate in York Centre.
He was appointed to the Senate by Paul Martin on March 24, 2005. He is currently the Deputy Chair of the Standing Committee on Social Affairs, Science and Technology, and a member of the Senate Committee on National Finance. He was co-opted to the Bureau of Liberal International as a Vice President at the 185th Executive Committee in Cape Town, South Africa in November 2010.
On January 29, 2014, Liberal Party leader Justin Trudeau announced all Liberal Senators, including Eggleton, were removed from the Liberal caucus, and would continue sitting as Independents. The Senators will refer to themselves as the Senate Liberal Caucus even though they are no longer members of the parliamentary Liberal caucus.
Eggleton's recent focus has been Toronto's community housing. On the Social Affairs Committee he has been instrumental in studies and reports on such matters as poverty, housing, and homelessness; early learning and child care; autism; the Health Accord; prescription pharmaceuticals; obesity; and dementia. In 2012, he founded the All-Party, Anti-Poverty Caucus.