Selected by the Nashville Predators with the No. 4 pick of the 2013 NHL Draft, Jones made the immediate jump to the NHL and scored 25 points (six goals, 19 assists) in 77 games and finished third on the Predators with 99 blocked shots.

Forty games into the 2015-16 season, Jones was traded by the Predators to the Blue Jackets for center Ryan Johansen on Jan. 6. Jones played 41 games for Columbus that season and scored 20 points (two goals, 18 assists).

Slated to be a restricted free agent in the summer of 2016, Jones signed a six-year contract extension with the Blue Jackets on June 29. He averaged 12 goals and 48 points for the next three seasons.

Jones set NHL career highs for goals (16), assists (41) and points (57) with the Blue Jackets in 2017-18, was named to the NHL All-Star Game for the second straight season and was also named an NHL Second Team All-Star.

He had 46 points (nine goals, 37 assists) in 2018-19 and helped Columbus win a Stanley Cup Playoff series for the first time, a four-game sweep against the Tampa Bay Lightning. Jones finished with nine points (three goals, six assists) in 10 playoff games.

Jones was selected to play in the NHL All-Star Game for the third time in 2020.

On July 23, 2021, Jones was traded by the Blue Jackets to the Chicago Blackhawks for defenseman Adam Boqvist and three draft picks, and five days later he signed an eight-year contract. On Nov. 17, 2021, Seth and his brother, Caleb Jones, played in a game as NHL teammates for the first time when the Blackhawks defeated the Seattle Kraken, 4-2.

After four seasons in Chicago, Jones was traded to the Florida Panthers on March 1, 2025, with a fourth-round pick in the 2026 NHL Draft, for Spencer Knight and a conditional first-round pick in the 2026 draft, Panthers general manager Bill Zito calling him, "one of the most consistent players of the past decade serving as a reliable workhorse on both sides of the puck."

Jones had nine points (four goals, five assists) and was plus-11 in 23 playoff games for the Panthers, who won the Stanley Cup for the second consecutive season. He led Florida in time on ice per game and was 10th among all defensemen in the playoffs (25:30), and was the third player to hoist the Cup following captain Aleksander Barkov and defenseman Nate Schmidt, who also won the Cup for the first time in his career.

On the international stage, Jones scored seven points (one goal, six assists) in seven games and was an alternate captain for the United States, which won the 2013 IIHF World Junior Championship. He also represented Team North America at the World Cup of Hockey 2016.

Jones was named to Team USA's roster for the Olympic Winter Games Milano Cortina 2026 but replaced by Anaheim Ducks defenseman Jackson LaCombe because of an injury sustained at the 2026 Discover NHL Winter Classic.

He is the son of former NBA player Popeye Jones. His brother, Caleb, was selected in the fourth round (No. 117) by the Edmonton Oilers in the 2015 NHL Draft.