Clark vaulted into national attention in 1976 when he emerged as the surprise winner of the convention to choose a new leader of the Conservative party. He had not been favoured to win but the convention was divided over the two leading candidates, Brian Mulroney and Claude Wagner. In May 1979 the Conservatives and Clark defeated the government of Pierre Trudeau and Clark became Canada's sixteenth prime minister. He was the youngest person to become prime minister (aged 40) and the first native-born Westerner.

Clark had only gained a minority government, that is, the Conservatives had more seats than the Liberals, but not enough to govern without the support of the other parties, especially the NDP. He decided to press ahead with his program, which included the selling off of the government-owned oil company, Petro-Canada, and cutbacks in government spending. The NDP combined with the Liberals to defeat the Conservatives in the House of Commons. Clark called an election and was defeated by a rejuvenated Pierre Trudeau in February 1980. Hence, Clark's time as prime minister was only nine months.

Clark was leader of the Opposition from 1980 to 1983, during which time he fought Trudeau's plans for a new constitution until agreement was reached with the provinces. Although Clark and his party led the polls, many in his party believed that he could not win another election. He chose to settle the question of his leadership at a convention in June 1983, but lost to Brian MULRONEY on the fourth ballot.

After Mulroney became prime minister in 1984, he made Clark secretary of state for external affairs. In April 1991, Mulroney named Clark minister responsible for constitutional affairs and gave Clark the difficult task of patching together an agreement with the provinces after the failure of the MEECH LAKE ACCORD. His efforts were met with lukewarm responses by many, including Mulroney. After the CHARLOTTEOWN ACCORD was rejected, Clark announced that the long constitutional debate had been exhausting for him and he was going to retire from politics.

After several years of retirement, Clark found non-political life unsatisfying and decided to return to politics in the spring of 1998. He replaced Jean CHAREST, who left the federal Conservatives to join the Quebec Liberals, and once again became the leader of the party. At the time of his return the party was $10 million in debt and had declined to fifth-party status. In addition, he did not support the United Alternative Movement to create a partnership among right-wing parties. In the 2000 federal election, the Progressive Conservatives failed to improve their status. In the years following the election, attempts by the Conservatives and the CANADIAN ALLIANCE to unite the right have been unsuccessful.

In 2003, Clark announced his resignation as leader but wished to maintain his MP seat for Calgary Centre. He was succeeded by Peter Mackay on 31 May 2003.