Yedlin was a product of O'Dea High School in Seattle, and was part of Washington Youth Soccer's State Olympic Development Program (ODP) from 2006 to 2009.

[5] Seattle Sounders youth director Darren Sawatzky first saw him play at age 11 and later said that Yedlin was "an offensive player at the time, he was tricky, he had explosiveness and could run for days."

Seattle Sounders FC sporting director Chris Henderson said of Yedlin: "DeAndre has great quickness and speed.

"[6] On February 8, 2011, Yedlin signed a letter of intent to play college soccer at the University of Akron under coach Caleb Porter.

[7][8] In his first year, Yedlin started in 20 of his 23 games for the Zips, playing alongside future professionals Wil Trapp, Darren Mattocks, Aodhan Quinn, and Scott Caldwell.

[12] On January 11, 2013, after two seasons with Akron, Yedlin signed with Seattle Sounders FC as the club's first homegrown player.

[14] Yedlin was named to the MLS Team of the Week for his performance, becoming the first rookie to earn the honor in his professional debut.

[15] On March 12, Yedlin shined and scored his first professional goal for the club in a 3–1 win against Tigres in the second leg of the Sounders 3–2 CONCACAF Champions League quarterfinal aggregate victory.

[34] On March 19, Yedlin scored his first goal for the club, his first since 2019, conceded a penalty, and was sent off in a dramatic 3–4 defeat at home to Çaykur Rizespor.

[36] Yedlin joined Inter Miami CF on February 2, 2022, on a four-year contract with an additional one-year option.

"[1] De Andre Yedlin was the vice captain of the squad which won Inter Miami 's first ever trophy , the 2023 Leagues Cup .

[38] When asked about the decision to leave a team led by Lionel Messi and Luis Suarez to join FC Cincinnati, Yedlin responded that he and his wife were attracted to Cincinnati as it is a great place to raise a family and has TQL Stadium, which he considered to be the best soccer specific stadium in the United States.

[43] After impressing in January and April, Yedlin was a surprise inclusion by US manager Jurgen Klinsmann on the U.S. final 23-man roster for the 2014 FIFA World Cup.

In the round of 16 match against Belgium, Yedlin came on as an early substitute for the injured Fabian Johnson, providing most of the vertical threat for the Americans.

Yedlin continued to play regularly as a right back under 2018 caretaker manager Dave Sarachan, taking on a leadership role in the new cycle as one of the few players carried over.

Sometimes he’s a shoulder to cry on or talk to, other times he’s a motivator.” “There’s a queue of questions people have for DeAndre,” said Tyler Adams, the USMNT captain in Qatar.

The report said that the situation became untenable and that it had to be addressed multiple times by players and coaches, after which Reyna eventually apologized to his teammates for his lack of effort.

After the apology, several players on the team spoke up to hold Reyna accountable for his actions, and the 20-year-old turned a corner in regards to his effort in training, per the sources in the report.

[60] During the 2020–2023 racial unrest in the United States, caused by the police murder of George Floyd, Yedlin was an outspoken supporter of the Black Lives Matter movement, asking if there was truly "liberty and justice" for all Americans and recalling the memories of his grandparents who had lived under the Jim Crow system of racial oppression.

[61] Yedlin spoke about the country's long history of police brutality against African Americans: "as a young black man in America it's one of those things you just grow up with.