In 2008, Josi was one of just four 17-year-olds to play in Switzerland's top division. During the 2010 NLA playoffs, Josi led all defensemen and tied for fourth overall in goals as SC Bern won the Championship title.
Following the championship win, Josi joined the Predators' organization for the 2010–11 season. He played his first season with the Predators' American Hockey League affiliate, the Milwaukee Admirals, before becoming a mainstay in the Predators lineup during the 2011–12 NHL season. During his NHL career, Josi has set and broken numerous franchise records. In 2019–20, Josi became the first Swiss player and the first player in Predators' franchise history to win the James Norris Memorial Trophy as the league's best defenceman. In 2021 he surpassed Mark Streit as the highest-scoring Swiss-born NHL player. In March 2023, Josi became the second-fastest active defenseman to reach 600 points in his NHL career. While he reached this milestone in his 823rd game, Josi also set a new franchise record for most 40-assist seasons. Josi subsequently became the second defenseman to lead an active NHL franchise in points, joining Ray Bourque. He is widely considered one of the best defencemen of his generation.