Niederreiter became Switzerland's highest NHL draft pick when the New York Islanders selected him No. 5 in the 2010 NHL Draft.

He became the youngest player in Islanders history when he made his NHL debut on Oct. 9, 2010. Four days later, at the age of 18 years and 35 days, Niederreiter became the fifth-youngest player of the NHL expansion era (1967-68) to score a goal.

Niederreiter was traded by the Islanders to the Minnesota Wild for forward Cal Clutterbuck and a third-round draft pick at the 2013 NHL Draft (goalie Eamon McAdam) on June 30, 2013. He scored 36 points (14 goals, 22 assists) in 2013-14, then scored at least 20 goals in each of the next three seasons. His goal at 5:02 of overtime in Game 7 of the 2014 Western Conference First Round gave the Wild a 4-3 win against the Colorado Avalanche.

He scored 23 points (nine goals, 14 assists) in 46 games for Minnesota the following season before he was traded to Carolina for center Victor Rask on Jan. 17, 2019. He scored four points (one goal, three assists) in 15 playoff games, helping the Hurricanes reach the Eastern Conference Final.

Niederreiter signed a two-year, $8 million contract with the Nashville Predators on July 21, 2022. He had 28 points (18 goals, 10 assists) in 56 games before he was traded to the Winnipeg Jets on Feb 25, 2023, for a second-round pick in the 2024 NHL Draft. He signed a three-year, $12 million contract (average annual value of $4 million) with the Jets on Dec. 4 that begins with the 2023-24 season.

Niederreiter became the first Switzerland-born player to skate 1,000 games in the NHL when he was plus-1 in 15:45 of ice time to help the Jets defeat the Washington Capitals 5-1 at Canada Life Centre on Dec. 13, 2025. He was named to Team Switzerland's roster for the Olympic Winter Games Milano Cortina 2026.