One of many NHL defenseman who were groomed as juniors by Kelowna of the Western Hockey League, Schenn was a Second All-Star Team selection in 2007-08 and played in the CHL Top Prospects game.

Schenn was selected by the Toronto Maple Leafs with the No. 5 pick in the 2008 NHL Draft and made his NHL debut Oct. 9, 2008, against the Detroit Red Wings. He recorded his first NHL point with an assist Oct. 29, 2008, against the New Jersey Devils, and scored his first NHL goal Feb. 7, 2009, against the Montreal Canadiens.

He was picked to play in the Young Stars Game at the NHL All-Star Game during the 2008-09 season. Collecting two goals and 14 points in 70 games, Schenn was selected to the NHL All-Rookie team.

Appearing in 79 games with the Leafs in 2009-10, Schenn led the team in hits (173) and was second in blocked shots (116). He scored five goals in 2009-10 and 2010-11, and topped the 20-point plateau in 2010-11 and 2011-12. Schenn led all NHL defensemen with 251 hits in 2010-11 and was first on the Leafs with 168 blocked shots.

On June 23, 2012, the Leafs traded Schenn to the Philadelphia Flyers. The move reunited Schenn with his younger brother, Flyers forward Brayden Schenn.

Schenn finished the 2012-13 season with 187 hits, tied for third in the NHL. Schenn played 32:51 for the Flyers in an April 15, 2012 game at Montreal, the most minutes a Philadelphia player had skated in a game since Eric Desjardins played 33:14 on Feb. 27, 2001.

Schenn played his 400th NHL game Jan 12, 2014, against the New York Rangers. He finished the 2013-14 campaign with 260 hits to lead the Flyers and finish sixth in the NHL. On Oct. 18, 2014, against the Dallas Stars, Luke assisted on a goal by Brayden, the first time the two brothers had ever combined for a goal in the NHL. They reversed roles Nov. 4, 2014, against the Edmonton Oilers, when Brayden setting up a goal for Luke, which was Luke's 100th NHL point.

On Jan. 6, 2016, the Flyers traded Schenn to the Los Angeles Kings. On July 23, 2016, Schenn signed a free agent contract with the Arizona Coyotes. After two seasons, he joined the Anaheim Ducks as a free agent, then was traded to the Vancouver Canucks on Jan. 17, 2019.

Schenn finished the season with the Canucks, then became a free agent again and was signed by the Tampa Bay Lightning on July 1, 2019. He was sent to Syracuse of the American Hockey League before injuries created openings on Tampa Bay's blue line. He played 25 games with the Lightning, scoring one goal and finishing with three points in 2019-20, then contributing two assists in 11 postseason games to help Tampa Bay win the Stanley Cup. He left Tampa Bay as a free agent following a second consecutive Stanley Cup championship to sign a two-year contract with the Canucks on July 28, 2021.

Schenn had 38 points (eight goals, 30 assists) in 121 games for the Canucks until he was traded to the Maple Leafs on Feb. 28, 2023, for a third-round pick in the 2023 NHL Draft. He signed a three-year, $8.25 million contract ($2.75 million average annual value) with the Nashville Predators on July 1 after two seasons in Vancouver, and played his 1,000th NHL game Oct. 17, 2024, Nashville's 4-2 loss to the Edmonton Oilers at Bridgestone Arena. Brayden played his 1,000th game Oct. 17, a 5-2 win for the St. Louis Blues at the Washington Capitals, making the Schenns the eighth set of brothers to each reach the milestone and first to do so in the same season.

He was traded to the Pittsburgh Penguins on March 5, 2025, and two days later to the Winnipeg Jets.

Before Luke joined the NHL, he helped Canada finish first at the 2008 IIHF World Junior Championship. He also helped Canada come in second at the 2009 IIHF World Championship.