Ekholm had plenty of success before playing his first NHL game during the 2011-12 season, more than two years after the Nashville Predators selected him in the fourth round (No. 102) of the 2009 NHL Draft.

The defenseman had already won a gold medal with Sweden at the 2008 Ivan Hlinka Memorial Cup; played for his country at the 2008 IIHF World Under-18 Championship; led junior-aged skaters in the Swedish second division with 21 assists in 2009-10; won a bronze medal with the Swedes at the 2010 World Junior Championship; and been named the top rookie in the Swedish Elite League in 2010-11, when he tied for fourth among defensemen with 10 goals and 33 points.

Ekholm made his NHL debut with the Predators on Oct. 13, 2011, against the Phoenix Coyotes and also played against the Vancouver Canucks on Oct. 20 before being assigned to Brynas of the Swedish Elite League on Oct. 22. He won the 2012 Borje Salming Award as the top defenseman in the league as he helped Brynas win the championship. During the playoffs Ekholm tied for the lead among defensemen with nine points and led all players at his position with eight assists.

Playing in the American Hockey League in 2012-13, he led Milwaukee defensemen in points (32) and tied for the league lead among defensemen with seven power-play goals. Ekholm played his only NHL game of the 2012-13 season for Nashville on April 15, 2013, against Vancouver.

Ekholm ranked 12th among NHL rookie defensemen in both games played (62) and minutes played (1,042:38) in 2013-14 and finished 18th among rookie defensemen in points (nine) and assists (eight). He was one of six at his position to play at least 50 games and have 10 or fewer penalty minutes. He got his first NHL point with an assist against the St. Louis Blues on Oct. 26, 2013, to begin a four-game assist streak.

Ekholm made his Stanley Cup Playoff debut in 2014-15, appearing in all six of Nashville's postseason games and scoring a goal in Game 3 of the first round against the Chicago Blackhawks. He had seven goals and 18 points in 80 regular-season games that season, including five goals and 13 points on the road. In 2015-16 he played all 82 games for the first time.

After reaching double figures in goals for the first time with 10 in 2017-18, Ekholm had 44 points (eight goals, 36 assists) and was plus-27 in 2018-19.

Ekholm signed a four-year, $25 million contract with Nashville on Oct. 13, 2021, and played two more seasons there before he was traded with a sixth-round pick in the 2024 NHL Draft to the Edmonton Oilers on Feb. 28, 2023, for defenseman Tyson Barrie, forward Reid Schaefer a first-round pick in the 2023 NHL Draft and fourth-round pick in 2024. He left Nashville fourth in team history among defensemen with 206 assists and 268 points, and third with 719 games played. His plus-104 rating was second behind Ryan Ellis (plus-114).

Ekholm had 45 points (11 goals, 34 assists) and led the Oilers at plus-44 during his second season in Edmonton. He averaged 21:57 of ice time in the playoffs and became the second defenseman in team history to score a goal in three straight games during the Western Conference Second Round against the Vancouver Canucks. His 68:49 of total short-handed time on ice helped the Oilers to Game 7 of the Stanley Cup Final, a 2-1 loss at the Florida Panthers.

Ekholm had one assist in three games for Sweden at the 4 Nations Face-Off. He signed a three-year, $12 million contract (average annual value of $4 million) with the Oilers on Oct. 8.  2025. That season, he scored his first NHL hat trick in his 938th game to help Edmonton to a 7-4 win against the Anaheim Ducks at Rogers Place on Jan. 26, 2026. He entered the night with three multigoal games in his NHL career, the last coming March 21, 2024.