He faces steep odds, as well as challenges from within his own party, in a campaign against Isakson. The 71-year-old enjoys high name recognition, popularity across the aisle - and more than $5.5 million in his campaign stash.
The Republican also has faced questions about his health since he revealed in June that he has suffered from Parkinson's for about two years. He has maintained that the disease was in its earliest stages and said it would not jeopardize his ability to serve another six-year term.
Barksdale’s supporters point to the success of David Perdue, a former Fortune 500 chief executive and first cousin of the former governor who emerged from a crowded Republican primary and beat Michelle Nunn, a nonprofit head and daughter of ex-Sen. Sam Nunn, in November 2014.
They also hold out hope that the growing likelihood of Donald Trump or Ted Cruz securing the Republican presidential nomination could so rile up Democrats and alienate mainstream Republicans that it gives the party a chance to flip an otherwise safe GOP seat.
Both arguments have flaws, though. While Republicans have gravitated toward outsider candidates – Trump breezed to a victory in last week's Republican primary in Georgia - exit polls show an overwhelming majority of Georgia Democrats support contenders with political experience.
And Isakson has sought to make it difficult to tie him to Trump. While he's said he would support the billionaire if he emerged as the GOP nominee, he has remained unapologetic about working with Democrats.
Barksdale surfaced after a range of well-known veteran Democrats, including former Rep. John Barrow and ex-Atlanta Mayor Shirley Franklin, passed on a race to challenge Isakson. So have several considered to be rising stars in the party, such as state Rep. Stacey Evans, the Rev. Raphael Warnock and Michael Sterling, an official in Atlanta Mayor Kasim Reed's administration.
Still, a handful of other Democrats have come forward in recent days. Air Force veteran Jim Knox qualified to run Monday, and Alpharetta businessman John Coyne has filed federal paperwork to run for the seat. Another potential contender, former state Sen. Regina Thomas, has said she was considering a run.
More: Read more about Isakson's reelection strategy
More: Other Democrats come out of woodwork for Georgia Senate race