Handel bested Ossoff by 3.8 percentage points in the most expensive House race in history.
It was a much closer margin than the 20-plus point wins typically posted by former Rep. Tom Price -- whose departure to become Trump's health and human services secretary created the vacancy.
But it wasn't what Democrats who pumped $23 million into Ossoff's campaign so desperately craved: A win.
Handel's victory showed that even with Republicans in power, the GOP's message in recent election cycles -- focused largely on urging voters to reject House Democratic leader Nancy Pelosi -- remains potent.
The successful execution of that playbook could calm congressional Republicans' ruffled nerves as the GOP advances major legislation to overhaul the nation's health care system and eyes a massive reform of its tax structure.
It also calls into question whether Democrats can sustain the energy fueling the party's anti-Trump resistance after losses in four consecutive special elections -- including Kansas, Montana and South Carolina.
At a Hyatt Regency in northern Atlanta, more than 100 attendees cheered and celebrated Handel's victory.
A little after 10:30 p.m. ET, Handel took the stage and told supporters she'd received a call from Ossoff conceding the race.
"He was more than gracious and he thanked me for a spirited campaign. And I wish him and Alisha all the best in the new life that they are going to be starting," she said, referring to Ossoff's fiancee, Alisha Kramer.
Handel thanked Trump, who had tweeted his support for her campaign in recent days, by name -- prompting the crowd to interrupt with cheers and chants of "Trump, Trump, Trump."
"A special thanks to the President of the United States of America," she said. "And let's not forget, our equally great vice president, Mike Pence."
Handel also thanked House Speaker Paul Ryan and House Majority Whip Steve Scalise, who remains in the hospital recovering from the recent shooting at a GOP congressional baseball practice.
"Right up until that tragic day on the ballfield, Steve would drop me a text message every single week to make sure I was doing OK and hanging tough," Handel said. "He even called me 'the terminator' in one of them."
Handel issued a call for civility, saying that "we also need to lift up this nation so that we can find a more civil way to deal with our disagreements. Because in these United States of America, no one -- no one -- should ever feel their life threatened over their political beliefs."
Ossoff and Handel faced off Tuesday in what has become the most expensive House race in history, with the candidates, their parties and super PACs pouring more than $50 million combined into the effort to win a single House seat in the northern Atlanta suburbs.
More than 140,000 voters cast their ballots early -- an astounding number for a special election, and one that nearly matches presidential contests.
The race was viewed nationally as a gauge of whether Trump's sagging approval ratings are a drag on Republicans that could threaten the party's control of the House in the 2018 midterm elections.
Democrats, meanwhile, saw in Georgia an early test of their strategy of trying to win typically Republican seats in suburban areas -- districts that are relatively highly educated, wealthy and diverse.
Trump weighed in on Twitter late Monday and early Tuesday, attacking Ossoff for living just outside the district, claiming Ossoff will raise taxes and calling Handel a hard worker "who will never give up!"
With the inflated price tag and the 15-month lag time between the special election and the November 2018 midterms, the contest might not hold much predictive value.
But it did carry the potential to provide the winning party a huge psychic boost.
With Handel's win, Republicans on Capitol Hill are likely to feel they are on the right track -- helping the GOP's push for health care and tax reform legislation. It could also show House incumbents that they can separate themselves from Trump effectively on the campaign trail, and stave off a potential wave of retirements.
Ossoff and Handel were the top two finishers in an April 19 primary, advancing to the one-on-one runoff election.
The district has historically leaned heavily Republican. Price won each time he was on the ballot since 2004 with more than 60% of the vote. Mitt Romney carried the district by more than 23 points when he faced former President Barack Obama in 2012.
However, it was Trump's collapse -- besting Hillary Clinton by just 1.5 points in the district in 2016 -- that led Democrats to believe it could be in play.
It was the best shot the party had of the four House special elections this spring to win a seat that now belongs to Republicans. But in November 2018, Democrats are expected to have many better pick-up opportunities. According to the Cook Political Report's Partisan Voter Index, there are 71 Republican-held districts that have less GOP-leaning electorates than Georgia's 6th District.
Georgia was not the only special election that happened Tuesday. CNN projected just after 9 p.m. ET, Republican Ralph Norman will win the special election in the South Carolina 5th Congressional District, defeating Democrat Archie Parnell in a closer than expected race to fill Mick Mulvaney's seat.
This story has been updated to reflect the latest results.