Drafted out of the Quebec Major Junior Hockey League (QMJHL) first overall by the Pittsburgh Penguins in the 2003 NHL Entry Draft, Fleury played major junior for four seasons with the Cape Breton Screaming Eagles, earning both the Mike Bossy Trophy as the league's top prospect and the Telus Cup as the top defensive player in 2003.

[7] He appeared in his first NHL game on October 10, 2003, against the Los Angeles Kings, recording an impressive 46-save performance, which included a penalty shot save, in a 3–0 loss.

[9] Fleury shared time with goaltenders Jean-Sébastien Aubin and Sébastien Caron[10] and lived up to first-overall-pick expectations early, earning Rookie of the Month honours in October with a 2–2–2 record, 1.96 goals against average (GAA) and .943 save percentage.

[11] He was loaned to Team Canada for the 2004 World Junior Championships in December and, upon returning with a second consecutive silver medal, he was sent back to the QMJHL on January 29, 2004.

[10] In light of financial difficulties for the franchise, it is believed Fleury's $3 million contract bonus, which he would have potentially received if he stayed and met several performance goals, was a factor in the decision to return him to Cape Breton.

[12] Fleury finished the QMJHL season with Cape Breton in a first round elimination and was subsequently assigned to Pittsburgh's American Hockey League (AHL) affiliate, the Wilkes-Barre/Scranton Penguins, and appeared in two postseason games.

When NHL play resumed in 2005–06, Fleury started the season once more in the minors, but was quickly called up by Pittsburgh for a game against the Buffalo Sabres on October 10 to replace an injured Jocelyn Thibault.

[15][16][17] Despite playing behind a shaky defense, Fleury was able to impress the team management with his technique and performance and signed a two-year contract extension worth $2.59 million in the off-season.

Fleury started the 2007–08 season slowly, then won four straight games before suffering a high-ankle sprain against the Calgary Flames on December 6.

While sidelined, he decided to change the colour of his goaltending equipment from the bright yellow that had become his signature to plain white, to gain an optical advantage over shooters.

Upon his return from injury, Fleury helped the Penguins win the Atlantic Division, going 10–2–1 with a 1.45 GAA[22] en route to a 12–2 playoff run to the 2008 Stanley Cup Finals against the Detroit Red Wings.

[26] Fleury compiled a 35–18–7 record in 2008–09 to help the Penguins to a fourth-place finish in the Eastern Conference, entering the 2009 playoffs as the defending Prince of Wales champions.

In the deciding game seven, Fleury made a key breakaway glove save early in the contest against Capitals superstar Alexander Ovechkin, helping the Penguins eliminate Washington by a 6–2 score.

[36][37][38] With Sidney Crosby and Evgeni Malkin sidelined with injuries for much of the 2010–11 season, Fleury and the Penguins' defence were relied on to carry the team to the playoffs.

He finished with a record of 23–8, tying him for fourth in the league, while his save percentage and goals against average continued to place him in the top half of starting goaltenders.

Despite a marked improvement in his playoff performance over the prior year, the Penguins lost in the second round to the New York Rangers despite taking an early 3–1 lead in the series.

[49] On April 11, Fleury recorded his league leading tenth shutout in a 2–0 victory against the Buffalo Sabres to secure the last wild card spot in the East.

Despite the Penguins qualifying for the 2016 Stanley Cup playoffs, Fleury was unable to play due to post-concussion syndrome until Game 4 of the Eastern Conference Final against the Tampa Bay Lightning where he subbed in for Murray at the start of the third period.

[53] When Matt Murray was injured during warm-ups of Game 1 of the playoffs versus the Columbus Blue Jackets, Fleury took the starting position and led the Penguins to a 3–1 win.

On June 21, 2017, with the emergence of Matt Murray, Fleury willingly waived his no trade and no movement clauses to be left exposed by the Penguins for the 2017 NHL Expansion Draft, where he was subsequently selected by the Vegas Golden Knights.

[55] Pittsburgh also traded their second round pick in the 2020 Entry Draft as an incentive for Vegas to select Fleury, in order for the team to be relieved of his nearly $6 million cap hit.

[62] On May 6, after Fleury posted a shutout, the Golden Knights were able to move on to the Western Conference finals by beating the San Jose Sharks in Game 6 of their playoff series.

[68] With Vegas unable to find a stable backup, Fleury was frequently overplayed during the 2019–20 season, posting a 2.77 goals against average and .905 save percentage.

[69] Fleury played sparingly during the 2020 playoffs, largely serving as Lehner's backup as the Golden Knights returned to the conference finals, losing to the Dallas Stars in five games.

At the age of 36, Fleury recorded a career-best 1.98 goals against average and a .928 save percentage, helping the Golden Knights to their third final four appearance in four seasons.

[86] On July 7, 2022, Fleury opted to forgo free agency and signed a two-year, $7 million contract extension to remain with the Wild.

[87] The Wild's decision to extend Fleury caused conflict with Talbot, who was subsequently traded to the Ottawa Senators in exchange for Filip Gustavsson.

Although Canada was defeated by Russia 3–2 in the gold medal game, Fleury posted a 1.57 GAA and was named the Top Goaltender and tournament MVP.

With the game tied 3–3 with less than five minutes remaining in regulation, Fleury left his net to play the puck and avert a breakaway opportunity for Patrick O'Sullivan of Team USA.

[100] He did not play in the tournament, however, as the goaltending duties were split between Martin Brodeur and Roberto Luongo, but still received a gold medal as Canada defeated the United States 3–2 in the final.