The USA Hockey National Team Development Program (U.S. NTDP) and USA Hockey acknowledged Leddy as one of the best young players in the nation, but instead of heading to Ann Arbor, Michigan, to join the U.S. NTDP, Leddy chose to finish his high school career with his teammates, and returned to Eden Prairie for his senior year.

When he returned to the lineup Leddy scored his first career goal in his second game back in a win at Minnesota State University on December 5, 2009.

He was named WCHA Rookie of the Week after a three-point game against Colorado College on February 20, 2010, scoring the game-winning goal with two assists.

On February 12, 2010, the Minnesota Wild traded Leddy's NHL rights to the Chicago Blackhawks, along with Kim Johnsson in exchange for Cam Barker.

[6] University of Minnesota head coach Don Lucia stated in September 2009 that he foresaw Leddy spending at least two years in development with the Golden Gophers before making his transition to the NHL and a professional career.

[2] On July 27, 2010, it was reported by the Chicago Tribune that the Blackhawks had agreed to terms on a three-year, $2.7 million contract with defenseman Nick Leddy, who was to turn professional and leave the University of Minnesota after playing one season, according to his agent, Neil Sheehy.

[8] After ending the 2010–11 season, his rookie season in the NHL, with the defending Stanley Cup champion Blackhawks narrowly making the playoffs as the eighth and final seed in the West and Leddy playing in 46 games with four goals, three assists and seven points, Leddy made his Stanley Cup playoff debut in the first game in the first round against the Presidents' Trophy-winning Vancouver Canucks on April 13.

After playing all 48 games with six goals, 12 assists and 18 points recorded in the lockout-shortened 2012–13 season to help the Blackhawks clinch the Presidents' Trophy as the regular season champions, he was a member of the Blackhawks team that won the Stanley Cup by defeating the Boston Bruins in six games in the 2013 Stanley Cup Finals.

[12] On October 25, 2019, shortly into the 2019–20 season, Leddy registered two goals on goaltender Anders Nilsson in a 4-2 victory over the Ottawa Senators, including becoming the first Islanders defensemen in franchise history to score on a penalty shot.

[13][14] Following the pandemic-shortened 2020–21 season, Leddy, with one year remaining on his contract, was traded by to the Detroit Red Wings in exchange for Richard Pánik and a second-round pick in the 2021 NHL Entry Draft.