Johnson, the first overall pick in the 2006 NHL Entry Draft, was drafted by the Blues from USA Hockey's National Team Development Program and played one season at the University of Minnesota before joining the NHL with St. Louis in 2007–08.
Johnson played hockey for the Academy of Holy Angels in Richfield, Minnesota, where he starred in his two seasons as a freshman and sophomore at the prep school. In the 2003–04 season he led all defenseman in scoring with 13 goals and 34 points to be selected to the Missota All-Conference Team. As a 16-year old Johnson transferred to Ann Arbor, Michigan, to play for the National Team Development Program (NTDP).
In the 2004–05 season, he split time between the U.S. National under-17 and under-18 squads, compiling 26 points in 57 games, tops amongst defenseman. Having been scouted as being tailored to suit the professional ranks with his hybrid two-way style and physicality, Johnson continued his rise in development the following season with a team-leading 49 points in 47 games with the under-18's. While also having a major impact at the junior international stage, Johnson was selected first overall in the 2006 NHL Entry draft by the St. Louis Blues. He became the first American-born defenseman to be selected first overall without having played Canadian major junior or collegiate hockey. He joined a select group of five (now six) Americans to have been chosen first overall in an NHL Entry Draft, along with Rick DiPietro (2000), Bryan Berard (1995), Mike Modano (1988) and Brian Lawton (1983), Patrick Kane (2007), and Auston Matthews (2016).
Having committed to the University of Minnesota, Johnson also became the first Golden Gopher and Minnesotan to be taken first overall. Despite the willingness to turn professional, Johnson was not signed to a professional contract with the Blues, becoming the first player in 44 years to play college hockey after being selected No.1 overall. In his freshman campaign with the Golden Gophers during the 2006–07 season, Johnson quickly established a top defensive role and accumulated 4 goals and 24 points in 41 contests to lead all WCHA rookie defenseman and earn a selection to the WCHA All-Rookie Team. Johnson concluded his collegiate career after his freshman year when he was signed by the St. Louis Blues to a three-year, entry-level contract on April 20, 2007.
Johnson scored his first career NHL goal against Los Angeles Kings goaltender Jonathan Bernier on October 6, 2007. It was also the game-winning goal. He finished his rookie season averaging over 18 minutes of ice-time per game to go with 5 goals and 28 assists in 69 games.
On September 16, 2008, during a team golf outing, Johnson tore two ligaments in his right knee after getting his foot stuck between the brake and gas pedals of a golf cart. He missed the entire 2008-09 season as a result. After returning for the 2009-10 season, Johnson set new career-highs with 10 goals, 29 assists, and 39 points, as well as 79 penalty minutes.
On August 2, 2010, as a restricted free agent, Johnson re-signed with the Blues with a two-year, $5.2 million contract. In the following season, 2010–11, on February 19, 2011, he was traded to the Colorado Avalanche, along with Jay McClement and a conditional first-round pick (that Colorado used to select Duncan Siemens), in exchange for Chris Stewart, Kevin Shattenkirk and a conditional second-round pick, which St. Louis used to select Ty Rattie. Later that day, Johnson made his Avalanche debut at the HP Pavilion at San Jose in a 4–0 defeat to the San Jose Sharks. In his second game, Johnson faced his former team and posted his first goal as a member of the Avalanche in a 4–3 victory over the Blues on February 22, 2011.
On July 3, 2012, Johnson signed a four-year, $15 million extension with the Avalanche. He was selected to the 2015 NHL All-Star Game on January 10, 2015. At the time of his selection, he was leading all defensemen in goal-scoring.
On September 22, 2015, Johnson signed a seven-year, $42 million extension with the Avalanche, making him the highest paid player on the Avalanche roster and one of the highest paid defensemen in the NHL.
As a product of the US NTDP, Johnson first made his international debut for the United States at the 2005 World U17 Hockey Challenge. In the same year, he captured a gold medal as a 17-year-old at the 2005 World Under-18 Championships. Johnson scored ten points in six games the 2006 World Under-18 championships to help the U.S. retain the gold medal, and was selected as the Bob Johnson Award winner as the Best American player in international competition.
Johnson was a member of the U.S. junior team that won a bronze medal in the 2007 World Junior Ice Hockey Championships. He was named to the tournament's All-Star Team and was named the tournament's Best Defenseman. Johnson finished the tournament with four goals and six assists for ten points, becoming the first defenseman to lead the tournament in scoring.
Representing the senior U.S. team at the 2010 Winter Olympics in Vancouver, Johnson received a silver medal after losing in overtime to Canada in the final.
Johnson was chosen to participate in the 2016 World Cup of Hockey for Team USA