A member of the Republican Party, he previously served in the Georgia legislature and the United States House of Representatives.

He opened a real estate branch for Northside Realty and later served 22 years as the company's president.

After 6th District Congressman and Speaker of the House Newt Gingrich resigned, Isakson ran in the February 1999 special election to succeed him, winning by a 40-point margin.

With the backing of much of Georgia's Republican establishment, he won both the primary and general elections by wide margins.

[5][6] Isakson served in the Georgia Air National Guard from 1966 to 1972, leaving service as a staff sergeant.

[7] Isakson enrolled at the University of Georgia, where he became a member of the Sigma Alpha Epsilon social fraternity.

[8][9] Shortly after graduating from UGA, he opened the first Cobb County office of Northside Realty, a prominent Atlanta-area real estate firm that his father, Ed, helped to establish.

[10][better source needed] In 1974, Isakson first ran for the Georgia House of Representatives in an eastern Cobb County district and lost.

Congressman and Speaker of the House Newt Gingrich faced a revolt in his caucus after the Republicans lost five seats in the midterm elections.

He won the election with 65% of the vote, forty points ahead of the second-place finisher Christina Fawcett Jeffrey.

[25] During his tenure in the House of Representatives, Isakson served on the Committee on Education and the Workforce, aiding President Bush in passing the No Child Left Behind Act.

In the general election, he easily defeated the Democratic candidate, 4th District Congresswoman Denise Majette, by 18 points.

[43] In March 2017, Isakson—who was recovering from back surgery—came to the U.S. Capitol in a wheelchair to vote to repeal an Obama administration rule that had made it unlawful for states to bar abortion providers from receiving Title X funding.

[44] In July 2019, Isakson was one of eight senators to introduce the Agricultural Trucking Relief Act, a bill that would alter the definition of an agricultural commodity to include both horticultural and aquacultural products and promote a larger consistency in regulation through both federal and state agencies as part of an attempt to ease regulatory burdens on trucking and the agri-community.

"[46] In February 2018, in response to the Stoneman Douglas High School shooting, Isakson said, "We have to do everything we can within our powers to make sure it never happens again.

[48][better source needed] In 2019, Isakson voted to support President Donald Trump's national emergency declaration regarding border security.

[50] His wife is a watercolor artist,[51] and served as honorary co-chair for Marietta's Theatre in the Square playhouse in 2007.

[52] In June 2015, Isakson disclosed that he had been diagnosed with Parkinson's disease, but added that the diagnosis would not affect his 2016 re-election plans.