The Washington Capitals selected Vrana in the first round (No. 13) in the 2014 NHL Draft and signed him to a three-year, entry-level contract. After playing one more season in Sweden, Vrana joined Hershey of the American Hockey League in 2014-15.

Vrana, who had 34 points (16 goals, 18 assists) in 36 games with Hershey in 2015-16, played his first NHL game on Dec. 1, 2016, against the New York Islanders and scored his first NHL goal eight days later against the Buffalo Sabres.

Vrana made the Capitals at training camp in 2017 and finished with 27 points (13 goals, 14 assists) in 73 games, averaging 12:30 of ice time. He showed his potential during the 2018 Stanley Cup Playoffs, scoring the game-winning goal in Game 5 of the Eastern Conference Second Round against the Pittsburgh Penguins.

In total, Vrana had eight points (three goals, five assists), including two game-winning goals, in 23 playoff games during Washington's run to its first Stanley Cup championship in team history.

Vrana saw his role increase during the 2018-19 season and finished with 24 goals and 47 points, more of each that he'd had during his first two NHL seasons combined. He improved on those numbers in 2019-20, finishing with 25 goals, including six game-winners, and 52 points in 69 games.

Vrana was traded to the Detroit Red Wings on April 12, 2021, with Richard Panik, a first-round pick in 2021 NHL Draft and second-round pick in 2022 NHL Draft for Anthony Mantha. He played 42 games for Detroit until he was traded to the St. Louis Blues on March 3, 2023, for forward Dylan McLaughlin and a seventh-round pick in the 2025 NHL Draft. Vrana was reinstated from the NHL/NHLPA Player Assistance program on Dec. 16, 2022 and recalled from Grand Rapids of the American Hockey League on Feb. 14.

He returned to the Capitals after signing a one-year, $775,000 contract Oct. 8, 2024.