In a statement, the 74-year-old Isakson cited his battle with Parkinson's disease.
“I am leaving a job I love because my health challenges are taking their toll on me, my family and my staff," he said. "My Parkinson’s has been progressing, and I am continuing physical therapy to recover from a fall in July. In addition, this week I had surgery to remove a growth on my kidney."
Isakson last month was hospitalized following a fall at his Washington apartment that left him with fractured ribs.
"With the mounting health challenges I am facing, I have concluded that I will not be able to do the job over the long term in the manner the citizens of Georgia deserve," the longtime Georgia lawmaker said in his statement. "It goes against every fiber of my being to leave in the middle of my Senate term, but I know it’s the right thing to do on behalf of my state."
FILE – In this Feb. 14, 2019 file photo, Sen. Johnny Isakson, R-Ga., flanked by Rep. Buddy Carter R-Ga., left, and Sen. David Perdue, R-Ga., right, leads a meeting with the Georgia Ports Authority and the Army Corps of Engineers to request full funding for the Savannah Harbor Expansion Project in the 2020 federal budget, on Capitol Hill in Washington. (AP Photo/J. Scott Applewhite)
Isakson was first elected to public office in 1976, when he won a seat in the Georgia House of Representatives. He served in the Georgia House and Senate until he won a congressional seat in Georgia's 6th District. He was first elected to the Senate in 2005 and currently serves as the chairman of the Committee on Veterans' Affairs and the Select Committee on Ethics as well as chairing the Subcommittee on Employment and Workplace Safety.
Isakson revealed publicly in June 2015 that he had been diagnosed with Parkinson's disease, but said at the time it would not affect his re-election hopes or his work in in the Senate. He won re-election in June 2016, meaning that his seat in the Senate would have next been up for election in 2022.
With his resignation, Georgia Gov. Brian Kemp, a Republican, will now have to appoint a replacement for Isakson until a special election can be held in 2020. The winner of that election will serve the remaining two years of Isakson's term, and the winner of the 2022 election will serve a full six-year term.
Isakson's retirement also means that voters in Georgia will have to cast a ballot for both of the state's Senate seats next year as Sen. David Perdue, a Republican, is seeking a second term in office.