After the 1952 general election Zijlstra was appointed as Minister of Economic Affairs in the Drees II cabinet, taking office on 2 September 1952.

After Party Leader Jan Schouten announced his retirement, Zijlstra was selected as his successor on 23 April 1956.

Before the 1967 general election, Zijlstra indicated that he would not serve another term as prime minister and opted to accept the nomination as head of De Nederlandsche Bank.

Zijlstra was granted the honorary title of Minister of State on 30 April 1983 and continued to comment on political affairs as a statesman until his death from dementia-related illness at the age of 83.

After completing his secondary education, he studied at the Netherlands School of Economics, the predecessor of the Erasmus University Rotterdam.

His studies were interrupted twice: first by his period of military service and later when he had to go into hiding in 1942 after refusing to sign the loyalty oath required of students by the Nazi occupation authorities.

Following his ministerial career, Zijlstra returned to the Vrije Universiteit as professor of public finance, though he also served as a member of the Senate between 1963 and 1966.

On 11 March 1946, Zijlstra married his childhood sweetheart Hetty Bloksma (30 January 1921 – 19 November 2013).