He played in Major League Baseball (MLB) for the Philadelphia Phillies (2006–2015), Texas Rangers (2015–2018), Chicago Cubs (2018–2019), and Atlanta Braves (2020).

[13] In his Major League Baseball debut on May 12, he pitched five scoreless innings, allowed one hit, struck out seven batters and walked five while earning a no-decision against the Cincinnati Reds.

On August 14, 2006, Hamels had his best start of his rookie season, shutting out the New York Mets over eight innings and striking out nine in the Phillies' 13–0 victory.

[19] His tenacity came to fruition when, on April 21, 2007, Hamels pitched his first major league complete game, allowing one run on five hits and two walks while setting a career high with 15 strikeouts.

[21] On May 16, he carried a perfect game into the seventh inning, but then walked leadoff hitter Rickie Weeks and surrendered a home run to the next batter, J. J.

[28] In the first game of the National League Division Series, he started for the Phillies, but surrendered three runs, three hits, and an "uncharacteristic" four walks, while striking out seven in 6+2⁄3 innings; he was assessed the loss.

[30] Before the season began in March, Hamels made a complaint about the Phillies underpaying him, saying it was a "low blow" and he was "caught off-guard" with the gap between what he and his agent John Boggs felt was a fair reward for his performance in the previous season and what he was paid (the Phillies paid him US$500,000, barely above the minimum salary for MLB players despite Hamels' strong performance).

The Philadelphia chapter of the Baseball Writers' Association of America presented him the "Steve Carlton Most Valuable Pitcher" award for the second consecutive year.

[44] Ciccotti found no structural damage in his arm,[45] yet Hamels still did not pitch on Opening Day as expected; Myers did for the third consecutive season.

From June on, however, he returned to his previous form, recording two complete-game shutouts (tied for the NL-lead), striking out at least 10 batters in two separate games, and amassing a 21-inning scoreless streak from August 21 to September 6, while allowing just two home runs in his final eight starts.

[12] In July, the Phillies augmented their starting rotation by acquiring two former Cy Young Award winners in Cliff Lee and Pedro Martínez from a trade and a free agent signing respectively.

Hamels started Game 2 of the 2009 National League Division Series against the Colorado Rockies, allowing four earned runs through five innings to take the loss.

It's one of those things where, a year in, you just can't wait for a fresh start", comments that were criticized by manager Charlie Manuel but otherwise largely regarded as speaking out of frustration.

Hamels started Game 3 of the National League Division Series against the Cincinnati Reds and, for the first time in his postseason career, pitched a complete-game shutout.

[70] On July 3, when the rosters for the 2011 MLB All-Star Game in Phoenix, Arizona were broadcast on TBS, it was announced that Hamels was voted onto the National League team along with fellow pitchers and teammates Roy Halladay, Cliff Lee, Plácido Polanco, and Shane Victorino.

[74] He finished fifth in the Cy Young Award voting behind Clayton Kershaw, Roy Halladay, Cliff Lee, and Ian Kennedy, respectively.

Hamels had missed scheduled starts in August due to a stiff shoulder, and loose bodies were removed from his elbow to fix his problems.

[41] Before the 2013 season in spring training, manager Charlie Manuel named Hamels the 2013 opening day starter, which Matt Gelb of The Philadelphia Inquirer wrote was a "long time coming".

[84] In his first career opening day start on April 1 against the Atlanta Braves, Hamels surrendered five earned runs in five innings and took the loss.

[86] He lost his eighth start on May 27, declining to a record of 1–8, which one Sports Illustrated column attributed more to the Phillies poor offense than Hamels.

[95] Despite lack of run support contributing to a poor win–loss record, Hamels was among the best pitchers in the National League, and was even mentioned as a Cy Young candidate.

[100][101] The Boston Red Sox, Los Angeles Dodgers, Texas Rangers, Chicago Cubs, New York Yankees, and San Francisco Giants expressed interest in trading for him during the 2015 season.

[106] Hamels also joined Vida Blue, Mike Witt, Kent Mercker and Kevin Millwood as no-hit pitchers who also pitched in a combined no-hitter.

The Rangers were under .500 as late as August 3, but posted a winning record for the remainder of the 2015 season and eventually overtook the Houston Astros in September for the American League West division lead.

Hamels' positive effect on the Rangers was compared to that of the Toronto Blue Jays' David Price, another ace starting pitcher who helped spearhead a run to the postseason after blending in seamlessly with a struggling team who acquired him at the trade deadline.

[125] On August 4, 2021, Hamels was signed by the Los Angeles Dodgers for $1 million through the remainder of the 2021 season, plus $200,000 for each game he started in the major leagues.

[130] Hamels had originally intended to make starts with the Padres' Triple-A affiliate, the El Paso Chihuahuas, as part of his recovery.

In 2012, Fangraphs ranked Hamels as having the fourth best changeup in the game trailing only Jason Vargas, Tommy Milone, and Félix Hernández.

[135] Rangers pitching coach Mike Maddux said of Hamels, It's a difficult task to try to get young guys to throw changeups, because their whole amateur career is spent staring at the scout with the gun.

[137][138] Chipper Jones, who was a star third baseman for the rival Atlanta Braves commented that Hamels is the "best left hander in the National League ... you have to respect his fastball, and his change-up is devastating.