Sampaio was born in Lisbon on 18 September 1939. The Sampaio family lived abroad in the United States and the United Kingdom for some years, due to the professional activity of his father Arnaldo de Sampaio (1908–1984), a physician. His mother was Fernanda Bensaúde Branco (1908 – 15 February 2000). His maternal grandmother Sara Bensliman Bensaúde, who died in 1976, was a Sephardi Jew from Morocco of Portuguese origin, and his maternal grandfather Fernando Branco (1880–1940) was a naval officer of the Portuguese Navy and later the Foreign Minister of Portugal. Sampaio himself is agnostic, and does not consider himself a Jew. His brother is the teenage-psychiatrist and writer Daniel Sampaio [pt].

He attended the American School of Lisbon as a child. He started his political career as college student of the Faculty of Law of the University of Lisbon. Sampaio was involved in student resistance against the fascist Estado Novo regime and led the Lisbon students union between 1960 and 1961. Following his graduation in 1961, Sampaio started a career as a lawyer, often defending political prisoners.

After the Carnation Revolution of 25 April 1974, Sampaio founded the Movimento de Esquerda Socialista (MES) (Portuguese acronym for Socialist Left Movement) but abandoned the political project soon after. In 1978 he joined the Socialist Party, where he has been associated with the party’s left wing. He was first elected to Parliament as a deputy for Lisbon in 1979. Between 1979 and 1984 he was a member of the European Commission for Human Rights, where he developed important work on these topics. Between 1986 and 1987 he was president of the parliamentary bench of the Socialist Party. In 1989 he was elected president of this political group, an office he held until 1991. Also in 1989, Sampaio was elected the 62nd Mayor of Lisbon, a charge he took in 1990, and was re-elected in 1993, remaining in office until 1995.

In 1995, Jorge Sampaio announced his wish to run for the presidency of the Republic. He won the election of 14 January 1996 in the first round against former Prime Minister Aníbal Cavaco Silva and became President on 9 March. After a non-controversial first mandate, he was re-elected as President on 14 January 2001.

As President, Sampaio’s actions were focused on social and cultural affairs. In the international political scene, he oversaw the transfer of Macao’s sovereignty to China in December 1999 and he also gave important publicity to the cause of East Timor’s independence. In October 2003, he invited the presidents of Finland, Germany, as well as of soon-to-be EU members Hungary, Latvia and Poland to Arraiolos in order to discuss the consequences of the 2004 enlargement of the European Union and plans for a Constitution for Europe. Such conventions of non-executive presidents of EU member states have become a regular event, and have been dubbed Arraiolos meetings.

It is generally considered that Sampaio’s presidency were marked by a firm sense of prudence and moderation, an approach which earned him a remarkably uneventful first term in office. In 2004, however, his refusal to hold early elections following Social Democratic Prime Minister José Manuel Durão Barroso’s resignation met with vigorous protest from all left-wing parties and even led to the stepping down of Socialist leader Eduardo Ferro Rodrigues. Sampaio made this decision to ensure political stability at a time when the country was facing economic recession, and he appointed Pedro Santana Lopes as Prime Minister. However, only four months afterwards, on 30 November, Sampaio concluded that the new cabinet was not achieving the desired stability, but quite the opposite, and he therefore dissolved the Parliament, calling new elections for February 2005.

On 24 February 2005, Sampaio called on José Sócrates, as the nation’s next prime minister, to form a government.

Sampaio’s successor was chosen in the presidential election held on 22 January 2006. Aníbal Cavaco Silva, the man he defeated in 1996, succeeded Sampaio on 9 March 2006.

In May 2006, Sampaio was appointed by the United Nations Secretary-General as his first Special Envoy for the Global Plan to Stop Tuberculosis. In April 2007, current UN Secretary-General Ban Ki-moon designated him as High Representative for the Alliance of Civilizations, a position he held till September 2012.

In 2008, he was awarded the North-South Prize of the Council of Europe. In 2015, he was a recipient of the Nelson Rolihlahla Mandela Prize, along with Dr. Helena Ndume, in recognition for his role in the struggle for the restoration of democracy in Portugal, the pro bono defence of political prisoners, and for raising awareness of tuberculosis as UN Secretary-General’s first Special Envoy to Stop Tuberculosis.

In 2010, he participated in the jury for the Conflict Prevention Prize awarded every year by the Fondation Chirac.