During World War II, Ezer Weizman served in the Royal (British) Air Force and was stationed in France and in India. From 1946 to 1948, he was a member of the IZL (pre-state underground organization). In 1948, after the proclamation of the State, he served in the "Air Service," the predecessor of the Israel Air Force. During the War of Independence, he flew arms and supplies to the Negev and to the besieged Gush Etzion. That same year, Weizman was sent to Czechoslovakia for training to fly the "Messerschmidt" airplane and to fly one back to Israel. He continued to serve in the IAF until 1966, the last eight years as its Commander.

Though Weizman served as IDF Head of Operations and Deputy Chief of Staff in the years 1966-1969, his political background excluded his becoming Chief of Staff. After ending his military service, Weizman served as the Minister of Transport in the second National Unity Government under Levi Eshkol. For a short while, he was the Chairman of the Herut party's executive committee, but resigned in 1972 over a disagreement with Menahem Begin over the distribution of posts in the party leadership. Weizman returned to the Herut party in May 1973 and remained there until 1980. In 1977, he was elected as a member to the 9th Knesset, during which he served as the Defense Minister in Menahem Begin's first government. In this capacity, he played a pivotal role in the peace process with Egypt, and launched the Litani Operation in 1978. In 1978, he proposed the formation of a "National Peace Government" to help further the peace process, but his idea was rejected by Begin.

In May 1980, Weizman resigned from the government, formally over military budget cuts, but in fact because of his dissatisfaction with progress in the peace process. In November of that year, he was dismissed from the Herut party because he considered establishing a new party with Moshe Dayan, who had resigned from the government in the previous year.

From 1980 to 1984, Weizman took a break from political life and engaged in private business. In 1984, he established a new party called "Yahad" which attained three seats in the 1984 elections to the 11th Knesset. Yahad became part of the Labor Alignment, and was appointed Minister without Portfolio in the National Unity Government formed by Shimon Peres. In January 1985, Weizman was appointed Coordinator of Arab Affairs, and in this capacity, he helped the Arab sector and continued in the effort to normalize relations with Egypt.

In 1986, Ezer and his Yahad party officially joined the Israel Labor Party. When the Labor Party joined the National Unity Government with the Likud in 1988, he served as the Minister of Science and Technology. During this time, Yitzhak Shamir threatened to evict Weizman from the government over secret talks he was having with the PLO. Weizman continued in the government until the disbanding of the National Unity Government in 1992. At that time, he decided to distance himself from political life, and resigned from the Knesset.

In 1993, as Labor candidate, he was elected president by the Knesset. He has received much criticism for some of his political statements and his refusal to grant pardons to certain prisoners. Following the Declaration of Principles with the PLO and the lack of progress on peace with Syria, Weizman became more rigid in his political approach to the peace process. However, after the election of Prime Minister Netanyahu in 1996, and a crisis in the peace talks, he began to actively promote the peace process, even going as far as inviting PLO Chairman Yasser Arafat to his private home in Caesarea.

Despite the controversy over Ezer Weizman's political involvement, he was elected to a second presidential term in March 1998. For the first time in Israeli history, an acting president who ran for a second term was faced by an opponent (in this case, MK Shaul Amor). After Ehud Barak was elected Prime Minister, Ezer Weizman publicly supported an Israeli withdrawal from the Golan Heights in exchange for peace with Syria. This outspokenness incensed the political Opposition.

At the end of December 1999, an expose was publicized alleging that starting in 1988, Weizman received large sums of money without reporting it to the authorities. Though the State Attorney claimed that there is no legal basis for Weizman to stand trial (mostly due to the Law of Limitation), the affair brought about Weizman's early resignation from the presidency (in effect as of July 13, 2000).