After two outstanding seasons with the Peterborough Petes of the OHL, and because of being highly regarded for his outstanding speed as a defenseman, Pronger was selected second overall by the Hartford Whalers in the 1993 NHL Entry Draft. He made his debut in the 1993-94 NHL season, playing 81 games for the Whalers and earning a spot on the NHL All-Rookie Team. After a second season in Hartford, he was traded to the St. Louis Blues for star forward Brendan Shanahan on July 27, 1995.

In the early years of his St. Louis career, Pronger played under coach and general manager Mike Keenan. Keenan's guidance is often cited as a factor in Pronger's maturation. He would eventually also become the team's captain, from 1997-2003.

In his third season with St. Louis, at age 23, Pronger was again named to the All-Star team. That year Pronger also had a brief cardiac arrest during the 1998 Stanley Cup Playoffs when he was hit in the chest with a puck in a game against the Detroit Red Wings. Despite this he recovered and also played for the Canadian Olympic team in Nagano. In 1999-2000, Pronger recorded a career-high 62 points and a +52 rating. For his efforts, he won the Norris Trophy, the Hart Trophy, and was named to the All-Star team.

Pronger notched 47 points the next season, but appeared in only 51 games due to injury problems. In February 2002, he won a gold medal with the Canadian Olympic Team in the Winter Olympics in Salt Lake City. That same year in the NHL, he had another fine season and played in the All-Star Game once again. But injuries became a problem again in 2002-03, limiting him to just five games played. Pronger bounced back with another quality season in 2003-04. Following the 2004-05 NHL lockout and imposition of the NHL salary cap, the Blues traded Pronger to the Edmonton Oilers for defensemen Eric Brewer, Jeff Woywitka and Doug Lynch. While the Blues needed to reduce team salaries to make it easier to sell the team, the Oilers were able to sign Pronger to a five-year, $31.25 million contract.

Pronger was selected to play for Team Canada at the 2006 Winter Olympics, marking his third consecutive Olympic Games. The Oilers went to the Stanley Cup Final that same year. On June 5, 2006, in Game 1 of the Stanley Cup Finals against the Carolina Hurricanes, Pronger became the first player in NHL history to score a penalty shot goal in a Stanley Cup Final game. The Oilers lost in game seven, with Pronger scoring a team-leading 21 points (5 goals, 16 assists) in 24 games, as well as a team leading plus/minus rating of +10 during the playoffs.

On July 3, Pronger was traded to the Anaheim Ducks for forward Joffrey Lupul, defensive prospect Ladislav Smid, Anaheim's 2007 first-round draft pick (traded to the Phoenix Coyotes, picked Nick Ross), a conditional first-round draft pick (dependant on the Ducks reaching the Stanley Cup Finals in the next 3 years), and Anaheim's 2008 second-round draft pick.

In 2007, Pronger played an important role for the Ducks run as they clinched the Stanley Cup, while Pronger himself participates in the Finals for the second year in a row. With the Stanley Cup victory he became a member of the Triple Gold Club.