On the June 20 runoff, Ossoff was defeated by Handel, 51.78% to 48.22%. According to Atlanta Magazine, “while his percentage of the total vote remained steady from April to now, Ossoff garnered 32,220 more votes in those three months, a 34 percent increase … Ossoff and his allies might have scooped up nearly every Democrat vote there was to get—and it still wasn’t enough to overcome the GOP’s numerical advantage.” The New York Times reported that Ossoff “produced probably the strongest Democratic turnout in an off-year election in at least a decade”, “brought a surprising number of irregular young and nonwhite voters to the polls,” and nearly doubled youth turnout in the 6th district from the 2014 midterm election. However, according to The Atlanta Journal-Constitution, “surging Democratic turnout wasn’t enough to overcome heavy GOP voting in a district where Republicans far outnumber Democrats.” Following reports of the election results, Frank Bruni, in an op-ed for The New York Times, characterized the race as “demoralizing for Democrats”. This was as close as a Democrat had come to winning this district since it assumed its current configuration as a northern suburban district in 1992; Democratic challengers had won more than 40 percent of the vote only twice before.

In 2009, Ossoff graduated from Georgetown University’s School of Foreign Service with a Bachelor of Science degree. He attended classes taught by former U.S. secretary of state Madeleine Albright and former Israeli ambassador to the United States Michael Oren. Ossoff earned a Master of Science degree from the London School of Economics in 2013.

Ossoff worked as a national security staffer and aide to Representative Hank Johnson for five years. He had top-secret clearance for five months. He left Johnson’s office in 2012 to earn a master’s degree at the London School of Economics.

Since 2013, Ossoff has been managing director and CEO of Insight TWI, a London-based investigative television production company that works with reporters to create documentaries about corruption in foreign countries. The firm produced BBC investigations about ISIS war crimes and death squads in East Africa. Ossoff was also involved in producing a documentary about the staging of a play in Sierra Leone.

After learning that Tom Price of Georgia’s 6th congressional district had been appointed secretary of Health and Human Services, Ossoff announced his candidacy for this special election on January 5, 2017. Ossoff quickly emerged as the most viable Democratic candidate out of a large field of candidates. He was endorsed by prominent figures such as Congressmen Hank Johnson and John Lewis, and state House Democratic Leader Stacey Abrams. He also received public support from U.S. Senator and Democratic presidential candidate Bernie Sanders. Ossoff raised over $8.3 million by early April of that year.

On April 18, 2017, no candidate received 50% of the vote in the blanket primary (“jungle primary”). Ossoff led with about 48.1% of the vote, Republican candidate Karen Handel received 19.8%, while the remainder of votes were scattered for 16 other candidates. Because no candidate secured an absolute majority, the top two vote-getters, Ossoff and Handel, competed in a runoff election on June 20, 2017. Ossoff won all but 1% of the Democratic vote, while the Republican vote was more heavily split. Republicans collectively won 51.2% of the overall vote.

According to The New Yorker in 2017, Ossoff has “progressive positions on women’s issues and health care” and “moderate stances on jobs and security.” According to Matthew Yglesias of Vox in 2017, Ossoff ran an “Obama-style campaign”, and placed himself in the middle between grassroots progressive activists in the Democratic Party and the more conservative and moderate Blue Dog Democrats. According to The New York Times, Ossoff’s 2017 campaign distanced itself from the national Democratic Party. According to The Washington Post, the 2017 Ossoff campaign opted not to turn the special election into a referendum on Trump’s alleged scandals, but to focus on “policy decisions by the president and congressional Republicans.” The Atlanta Journal-Constitution wrote that Ossoff “often tried to avoid nationalizing that campaign over fears of losing moderate voters.”

On February 23, 2018, Ossoff announced he would not seek the seat in the regular election in 2018; the seat was won by Democrat Lucy McBath in November 2018.

Ossoff ran in the Democratic primary election to try to unseat incumbent Republican Senator David Perdue in the 2020 United States Senate election in Georgia. On June 10, Ossoff won 50.5% of the vote, just over the threshold to prevent a run-off election. He faced off against Perdue in the November general election, and neither candidate reached 50%, forcing a run-off election scheduled for January 5, 2021.

In July 2020, Perdue’s campaign ran a Facebook advertisement in which Ossoff’s nose was digitally altered to be larger, which Ossoff criticized as “one of the most classic anti-Semitic tropes.” Perdue’s campaign said that Perdue had not seen the image and that the widening and elongation of Ossoff’s nose was done by a vendor. The Perdue campaign pulled the advertisement.