When Dato Onn resigned as President of UMNO and Tunku Abdul Rahman became its new President, Tun Dr. Ismial fell under his spell and took to politics. Tun Suffian has said that the "trait in his character never to be false to his principles was later to shine like a beacon when he entered public life". Tun Dr. Ismail was nominated unofficial member of the Johore State Council as early as 1948 and subsequently entered the Johore Exco. He was then elected to the Johore Bahru Town Council where he soon mastered the intricacies of the Town Board Enactment and its By-laws. In 1952, he was appointed as unofficial member of the Federal Legislative Council. Soon afterwards, at the request of Tunku Abdul Rahman he was appointed Member for Lands and Mines in the Member system of Government. In 1955, when elections were held to the Federal Legislative Council, he was elected. From the same Johore Timor Constituency, he was re-elected to the Federal Legislature three time in 1959, in 1964 and in 1969. In 1956, when Tunku Abdul Rahman was Chief Minister, Tun Dr. Ismail was appointed Minister of Commerce and Industry. After Merdeka in 1957, he joined the First Cabinet and he held various portfolios.
He was also our first Ambassador in Washington D.C. and Malaysian representative to the United Nations. When he returned he re-joined the Cabinet and held the important portfolios of Internal Security and Home Affairs. He resigned from the Cabinet in June 1967 due to ill health but not from Parliament. He contested and returned to Parliament for a further term in 1969. After the incidents of may 13th 1969 he re-joined the Cabinet and in the words of Tun Suffian "it was during the agonising days that his outstanding qualities came to the fore. Perhaps it can be said that more than anybody else the Tun contributed substantially to the restoration of public confidence in the Government's determination to restore law and order after the May 13th incidents." When Tunku Abdul Rahman retired from the Premiership and passed his mantle to Tun Abdul Razak, Tun Dr. Ismail became the Deputy Prime Minister.
He was made Honorary Member of the Academy of Medicine of Malaysia in 1973. On 2nd August 1973, he passed away as a result of a heart attack.
The Tun Ismail Oration was inaugurated in his memory by the Academy of Medicine in 1974. The Kuok Foundation set up a fund, interest from which was given to the Academy to finance the Oration once in two years. The first oration was delivered by Yang Amat Arif Tun Mohamed Suffian bin Hashim, the then Lord President, in August 1974.
|6th Sept 1974||Yang Amat Arif Tun Mohamed Suffian b Hashim, Lord President of the Judiciary, on "Tun Dr. Ismail and his contributions"|
|19th Aug 1976||YAB Dato' Seri Dr. Mahathir Mohamad, Deputy Prime Minister, on "Coordination in higher Education"|
|30th Sept 1978||Dr. Patrick Ongley, President of the China Medical Board of New York, on "Organisational Responsibilities involved in the Granting of Post graduate Medical Diplomas and Degrees in Malaysia"|
|4th Dec 1980||YABhg Tun Tan Siew Sin (Deceased), Minister of Finance, on " National Unity"|
|8th Sept 1983||YB Tan Sri Dr. Tan Chee Khoon, former Leader of the Opposition, on " Malayanisation of the medical Services and Postgraduate Medical Education in Malaysia"|
|1st Aug 1985||YAB Dato' Musa Hitam, Deputy Prime Minisjter, on "Tun Dr. Ismail and the State of Malaysia"|
|15th Oct 1987||Ybhg Prof Tan Sri T.J. Danaraj, Founder Dean of the Faculty of Medicine, University Malaya on "The Experience of Medicine"|
|5th Oct 1989||Duli Yang Maha Mulia Seri paduka Baginda Yang Di-Pertuan Agong, Sultan Azlan Shah, on "Medicine, Ethics and Law"|
|3rd Oct 1991||Ybhg Mr. Robert Kuok Hock Nien on "A Vision of the Asian-Pacific Economies in the Year 2010"|