Den Uyl was appointed as Minister of Economic Affairs in the Cals Cabinet, taking office on 14 April 1965.

In the election of 1967 Den Uyl served as Lijsttrekker (top candidate) and became Parliamentary leader, taking office on 23 February 1967.

During the election of 1977 Den Uyl served as Lijsttrekker but following a difficult cabinet formation failed to create a new coalition.

Den Uyl left office following the installation of the First Van Agt Cabinet on 19 December 1977 but continued to serve in the House of Representatives as Parliamentary leader.

For the election of 1981 Den Uyl again served as Lijsttrekker and following a cabinet formation with his successor— the leader of the Christian Democratic Appeal, Dries van Agt— formed the Second Van Agt Cabinet with Den Uyl appointed as Deputy Prime Minister and Minister of Social Affairs and Employment, taking office on 11 September 1981.

For the election of 1982 Den Uyl again served as Lijsttrekker and returned to the House of Representatives as Parliamentary leader, taking office on 16 September 1982.

He holds the distinction as leading the most left-wing Dutch cabinet, and his premiership is seen as divisive with both scholars and the public, from considering him to have been average to him having been one of the best Prime Ministers since World War II.

Until 1945 he was a civil servant at the National Bureau for Prices of Chemical Products, part of the Ministry of Economic Affairs.

After World War II, Den Uyl worked for Het Parool, Vrij Nederland and other former resistance papers.

As the responsible minister, he decided to close the uneconomic coal mines in Limburg, causing high local unemployment.

Den Uyl said in a speech on national television that "things would never return to the way they were" and implemented fuel rationing and a ban on Sunday driving.

The government's budget deficit increased tenfold, inflation approached 10 percent, the unemployment rate doubled, and the current account went from positive to negative – the latter a critical problem in a country that rises or falls on foreign trade.

[10] The government also enacted a wide range of progressive social reforms, such as significant increases in welfare payments, the indexation of benefits and the minimum wage to contractual private sector wage developments[11] and a system of rent rebates (1975),[12] Kindergartens and primary schools with high percentages of children from lower income families were provided with extra facilities (including more money and teachers) and cooperation was stimulated between schools and social and cultural institutions.

[15] The number of years of full compulsory education were increased,[16] and an Act on equal pay in the private sector was introduced.

[19] From 1 January 1975, the elderly “who rely solely or almost exclusively on the AOW pension have been granted an additional reduction of NLG 18 per month on the premium for health insurance for the elderly.”[20] Also, with retroactive effect from 1 July 1975, “a new regulation for relocation and refurbishment costs applies to elderly people who want to move from a cheaper to a more expensive home.”[21] In 1975 the social assistance standard was again structurally increased for incomplete families.

[31] The National Standardization Decree of 3 July 1974 provided rules for the provision of assistance for generally necessary subsistence costs.

A social minimum now applied to various types of households: a standard amount that was considered sufficient to cover the general necessary costs of existence.

"[40] Also, as noted by another study, "Partly under the influence of the increase in unemployment since the oil crisis of 1973, a hardship clause was added to the Social Security Act in July 1974 through a change in the National Standards Decree.

1974, 825) “envisaged exemption from (part of) the assets of a former self-employed person in the means test for social assistance.”[42] In September 1975, a regulation on the promotion of vocational training for young people was introduced, aimed at "a great number of young people who, as a result of the present educational system, depend on on-the-job training within the framework of the Apprenticeship Law."

[45] The Collective Redundancy (Notification) Act of 1976 imposed an obligation on employers (who intend to collectively dismiss employees) "to give written notice of this intention to the relevant trade unions for consultation,"[46] while that same year consultative works councils were replaced by powerful ones modelled after the German works councils.

In September 1977, regulations were issued "regarding the conditions under which young persons of 16 and over may exceptionally drive agricultural tractors."

The Labour Party won by a landslide, receiving over 33% percent of the votes, a relatively large share in the divided politics of the Netherlands at that time, and 53 seats.

However, its other coalition partner, the Political Party of Radicals, lost nearly all its seats, making it impossible for Den Uyl to form a new government that he could count on to support him in parliament.

As leader of the main opposition party, Den Uyl, always a soft-spoken Atlanticist, provided cover for the government's controversial decision to place NATO cruise missiles on Dutch soil.