On 1 September 1973 Van Mierlo unexpectedly announced he was stepping down as party leader, stating that he would not stand for the 1977 general election but would continue to serve in the House of Representatives as a frontbencher until the end of the parliamentary term.

For the 1986 general election Van Mierlo again served as lead candidate and returned to the House of Representatives as parliamentary leader on 3 June 1986.

For the 1989 and 1994 general elections Van Mierlo once again served as lead candidate, and following a successful cabinet formation with Labour Party leader Wim Kok and People's Party for Freedom and Democracy leader Frits Bolkestein formed the Kok I cabinet, with Van Mierlo appointed as Deputy Prime Minister and Minister of Foreign Affairs, taking office on 22 August 1994.

Shortly after the installation of the Kok II cabinet, Van Mierlo announced his retirement and resigned from the House of Representatives on 18 August 1998.

Van Mierlo was granted the honorary title of Minister of State on 24 October 1998 and continued to comment on political affairs as a statesman until his death in March 2010 from the complications of a Hepatitis C infection at the age of 78.

For the 1994 general election Van Mierlo, for the sixth time as lead candidate, won twenty four seats and the Democrats 66 became a major party in the House of Representatives.

After an arduous cabinet formation with the Labour Party and the People's Party for Freedom and Democracy (VVD), a deal was struck that resulted in the First Kok cabinet with Van Mierlo becoming Deputy Prime Minister and Minister of Foreign Affairs serving from 22 August 1994 until 3 August 1998.

Following the end of his active political career, Van Mierlo occupied numerous seats on supervisory boards on cultural organizations.

He was appointed Minister of State on 24 October 1998, a mainly honorary title for politicians with an extensive history of government service.

Since 1999 Van Mierlo had a relationship with the Dutch writer Connie Palmen; they got married on 11 November 2009, in Amsterdam.