Prior to seeking elected office, Pettigrew was director of the Political Committee, NATO Assembly, in Brussels, from 1976 to 1978, executive assistant to the Leader of the Quebec Liberal Party from 1978 to 1981 and Foreign Policy Advisor to Pierre Trudeau, Prime Minister of Canada, from 1981 to 1984.

Pettigrew was vice-president of Samson Bélair/Deloitte & Touche in Montreal from 1985 to 1995, where he acted as a business consultant to companies with dealings in international markets.

Pettigrew served in the Liberal cabinet of Jean Chrétien in various capacities and in the government of Paul Martin as Canada's Minister of Foreign Affairs.

Pettigrew previously ran for parliament in the 1984 federal election in the riding of Kamouraska—Rivière-du-Loup but was defeated by less than 7,000 votes by the Progressive Conservative candidate, André Plourde.

At the 2003 WTO Ministerial Conference in Cancún, Pettigrew played an aggressive role as chair of the working group on the Singapore issues, controversial sectors of proposed liberalization which were bitterly opposed by some developing nation delegates, not to mention masses of protesters outside of the gates where the meetings were held.

On April 26, 2005, the Montreal newspaper Le Devoir reported that the trilingual Pettigrew, who speaks English, French and Spanish, would leave Canadian politics to serve as the Secretary General of the Organization of American States.

In 1999, Pettigrew wrote Pour une politique de la confiance (English translation: The New Politics of Confidence), a book on globalization and the art of governing.

Engler claimed that the red paint was meant to symbolize the blood on the hands of the Canadian state due to Canada's involvement in Haiti.

[4][5] At the 2004 election, Pettigrew was nearly defeated by a Bloc Québécois challenger – only the second time that the Liberals' hold on the riding had been seriously threatened.

In August 2016, Pettigrew was appointed special envoy on the Comprehensive Economic and Trade Agreement between Canada and the European Union.