Only the second goalie to drafted first overall, the other being Rick DiPietro of the New York Islanders in 2000, Fleury was workhorse with Cape Breton in his three seasons with the team (2000-2003) and was stellar in goal for Canada at the 2003 World Junior Championships in Halifax, Nova Scotia. Even though, Canada came up short in the Gold Medal game against Russia, Fleury was named the tournaments Top Goaltender.

After a strong training camp, the Penguins opted to keep their first round pick as part of their opening night roster. Fleury went on to play 22 games with the Penguins during the 2003-04 season before the team opted to return him to his junior team in the second half of the season. While with the Pens, Fleury compiled a 4-14-2 record with a 3.64 goals against average on a young and rebuilding club and saw limited action with the team's AHL affiliate in Wilkes-Barre/Scranton.

Prior to rejoining his junior club, Fleury was lent to Canada's World Junior team for the 2004 World Junior Championships. For a second consecutive year, Fleury backstopped Canada to the Gold Medal game, only to come up short once again, falling to the favoured US team.

Fleury spent yet another season in Wilkes-Barre/Scranton during the NHL lockout as the Pittsburgh Penguins continued to rebuild their franchise. When play resumed in 2005-06, Fleury battled out of the AHL to grab the Penguins starting role. However, the Penguins finished last in the Eastern Conference that season and the club allowed a league-worst 316 goals as Fleury struggled to find his confidence.

Over the next two seasons, the play of both Fleury and the Penguins improved significantly. The club's line-up now featured rising superstars Sidney Crosby and Evgeni Malkin as the Penguins returned as an Eastern Conferece threat.

In his third full NHL season, Fleury missed 34 regular season games due to a high ankle sprain but returned to post a 10-2-4 record, leading the Penguins back into the playoffs. He continued his torrid play in the Stanley Cup playoffs, going 14-6 as the Penguins reached the Stanley Cup Final for the first time since 1992. After a hard-fought six-game Stanley Cup Final, Fleury and the star-studded Penguins were ousted on home ice by the Detroit Red Wings.

In 2008-09, Fleury and his Penguins would avenge their loss in the finals of the previous season by beating the Red Wings in a 7 game series that went right down to the wire. Battling back from a 2 games to none deficit, the Penguins would hoist Lord Stanley's Cup on the road, as Detroit had done a year earlier.

On the international stage, Fleury was part of the Canadian team that captured gold on home soil at the 2010 Olympic Winter Games in Vancouver.

During the 2015-16 season, Fleury recorded a career-best 2.29 goal-against-average and posted a solid .921 save percentage. However he suffered a late-season concussion and was not able to start the post-season with the Penguins. He did manage to appear in a pair playoff games for the club, as the Penguins marched to the fourth Stanley Cup title in franchise history.

Fleury would serve as the Penguins backup goaltender during the 2016-17 regular season, but would be thrust into the spotlight to begin the post-season. When Matt Murray was injured prior to the start of Game One of the first round series, Fleury took over in goal and helped the Penguins to a 3-1 victory. He would remain the Penguins' starter until mid-way through the Eastern Conference Final and prove to be a key contributor to the Penguin's second consecutive Stanley Cup title.

On June 21, 2017, Fleury's time in the Penguins' organization would come to an end. He was selected by the Vegas Golden Knights in the 2017 NHL Expansion Draft. Late in his first season in the desert, Fleury would record the 400th win of his NHL career in a 3-2 victory over the Philadelphia Flyers. At age 33, Fleury became the second youngest goaltender in history to accomplish the feat.