In 1974, Isakson first ran for the Georgia House of Representatives in an eastern Cobb County district and lost. He ran again in 1976 and won. He served seven terms in the House. He won re-election unopposed in 1984. and 1988. In his last four terms (1983–1990), he was the Republican Minority leader. In 1988, he was co-chair for U.S. Senator Bob Dole's presidential primary campaign. Isakson was the Republican candidate for Governor of Georgia in 1990. He won the Republican primary with 74% of the vote in a four candidate field. In the general election, he was defeated by Democratic Lieutenant Governor Zell Miller 53%–45%. His campaign was managed by Jay Morgan while Miller's campaign was managed by James Carville. Miller ran on a pledge to start a state lottery and use the revenue for public schools. Isakson proposed a ballot referendum on the lottery. In 1992, Isakson was elected to the Georgia Senate. In 1996, Isakson ran in the Republican primary for the U.S. Senate seat being vacated by retiring Democratic U.S. Senator Sam Nunn. During his campaign, Isakson expressed his support for abortion rights in a campaign advertisement. Isakson finished second in the primary election with 35% of the vote, but the winner Guy Millner, a millionaire businessman, failed to get a majority of the vote (receiving only 42%). Therefore, per Georgia law, he was forced into a primary runoff election. Millner defeated Isakson in the runoff 53%–47%. Millner lost the general election to Democrat Max Cleland. In December 1996, Isakson was appointed head of the State Board of Education by Gov. Zell Miller. In November 1998, 6th District U.S. Congressman and Speaker of the House Newt Gingrich faced a revolt in his caucus after the Republicans lost four seats in the midterm elections. Amid the turmoil, Gingrich announced on Friday after the Tuesday elections not only that he would not run for a third term as Speaker, but he would also not take his seat for an eleventh term beginning in January 1999. Isakson ran for the seat in a special election in February. He won the election with 65% of the vote, up forty points ahead of the second-place finisher Christina Fawcett Jeffrey. Isakson won re-election to his first full term with 75% of the vote. Isakson won re-election to his second full term with 80% of the vote.