With St. Louis, O'Reilly won the Stanley Cup in 2019 over the Boston Bruins and was awarded the Conn Smythe Trophy as the most valuable player in the 2019 playoffs, later being named captain in 2020.

He was credited with the goal after inadvertently deflecting Sharks defenceman Dan Boyle's pass attempt from an improbable angle into the net past goaltender Evgeni Nabokov to put the Avalanche ahead in the series, two games to one.

In the following year, 2011–12, having established himself as the leading defensive centre on the Avalanche, O'Reilly developed his two-way game and increased his offensive production playing alongside linemate Gabriel Landeskog.

[17] With the lock-out cancelling the start of the season, O'Reilly, in joining his brother Cal, signed a two-year contract with Russian Kontinental Hockey League (KHL) club Metallurg Magnitogorsk on December 7, 2012.

[19] Despite an end to NHL lock-out announced on January 12, 2013, O'Reilly was still unable to come to terms with the Avalanche and initially continued to play in Russia to miss the opening of the shortened 2012–13 season.

[20] At an impasse with the Avalanche a month into the season, O'Reilly was training with the OHL's London Knights when he ended his holdout on February 28 after signing a two-year, $10 million offer sheet with the Calgary Flames.

[21] With a game coinciding between the two clubs on that day, the Avalanche announced during the contest that they opted to forgo compensation and secured O'Reilly to a contract by matching the Flames' offer sheet.

[22] Due to O'Reilly having signed a contract with a KHL franchise, had Colorado not matched Calgary's offer sheet, he would have had to pass through waivers before returning to the NHL.

In the 2013–14 season, under new Head Coach Patrick Roy, O'Reilly was moved to the wing to play alongside centre Matt Duchene and subsequently responded with a team-leading—and career-high—28 goals and 64 points in 80 games as the Avalanche returned to the playoffs.

For the second time in his career, O'Reilly led the NHL in takeaways with 83 and, in recording just one penalty minor, was awarded the Lady Byng Memorial Trophy for gentlemanly conduct and sportsmanship by the League.

[25] During the 2014–15 season, O'Reilly scored 17 goals and 38 assists for 55 points, also leading the Avalanche in average ice time per game, as Colorado failed to make the 2015 playoffs.

[26] On June 26, 2015, the Avalanche traded O'Reilly, alongside Jamie McGinn, to the Buffalo Sabres in exchange for Nikita Zadorov, forward Mikhail Grigorenko, prospect J. T. Compher and the 31st pick in the 2015 NHL Entry Draft.

[30] In spite of his personal success, the Sabres failed to qualify for the NHL playoffs during his tenure, resulting in O'Reilly admitting he began to lose his love of the game.

[31] His comments seemed to polarize fans in Buffalo, with many subsequently labeling O'Reilly a cancerous presence on the team, while others defended his remarks and agreed that the Sabres had become complacent with losing.

[38] For his excellent two-way play during the season, O'Reilly won the Frank J. Selke Trophy as the league's best defensive forward on June 19, 2019, over Patrice Bergeron of the Boston Bruins and Mark Stone of the Vegas Golden Knights.

[41] On January 11, 2020, O'Reilly, as well as fellow Blues teammates Alex Pietrangelo, Jordan Binnington, and David Perron, were invited to the 2020 National Hockey League All-Star Game.

[43] With the Blues out of the playoffs picture during the 2022–23 season and O'Reilly an impending unrestricted free-agent, rumours began to circulate regarding a potential trade out of St. Louis for the team to recoup some assets.

[48] O'Reilly made his international debut at the 2008 World U-17 Hockey Challenge, scoring six points in six games as captain of gold medal-winning Team Ontario.

[52] Unable to reach the playoffs with the Avalanche after the 2014–15 regular season, O'Reilly, for the third time in his professional career, was invited to participate in the 2015 IIHF World Championship in the Czech Republic.