He played in Major League Baseball (MLB) for the Baltimore Orioles, Chicago Cubs, Philadelphia Phillies, and San Diego Padres.

One Oriole discovered this blog and printed out excerpts that he displayed around the clubhouse; this discovery caused friction between Arrieta and the rest of the team.

[20] He opened the regular season with the Double-A Bowie Baysox, posting a 6–3 record with a 2.59 ERA in 11 starts before receiving a promotion to the Triple-A Norfolk Tides on June 12.

[10] Although he took the loss in his 2–0 club debut against the Indianapolis Indians, Arrieta pitched six solid innings for Norfolk, allowing only two hits and one solo home run.

[24] Arrieta received his chance shortly afterwards, replacing a struggling Brad Bergesen for a June 10 game against A. J. Burnett and the New York Yankees.

[31] He began the season as one of Baltimore's best starters, leading the team with nine wins in 18 starts, but there was some concern over his health and command: his ERA was 4.90 in that same time frame, he rarely lasted beyond six innings, and he frequently walked batters.

[33] The fibrous mass in his elbow continued to affect his command, however, to the point where he walked a career-high six batters in a game against the New York Yankees.

[34][35] Arrieta underwent a season-ending surgery to remove the mass on August 12, and he finished his sophomore season with a 10–8 record and 5.05 ERA in 22 starts.

Manager Buck Showalter told reporters, "I think our guys understand that carrying around 6.00 ERAs in the American League just don't cut it".

[40] After a minor-league start in which he allowed five earned runs in 3+2⁄3 innings against the Gwinnett Stripers, Arrieta acquired a sport psychologist to aid in the mental aspect of his pitching.

[45] Arrieta outpitched both Brian Matusz and Steve Johnson during spring training to win back a position in the Orioles' 2013 Opening Day starting rotation.

[49] He was first called up to Chicago for a spot start in the second game of a doubleheader against the Milwaukee Brewers, but did not join the Cubs full-time until August 14, when he replaced a struggling Carlos Villanueva in the rotation.

Sandy Koufax had been the last pitcher to complete a no-hitter by striking out all three batters he faced in the ninth inning, doing so against the Cubs in his 1965 perfect game—a game also played at Dodger Stadium.

The right-hander held opposing hitters to a .130 batting average and a .196 on-base percentage in August and struck out 43 batters while walking just 10.

[81] The Arizona Diamondbacks defeated Arrieta and the Cubs 3–2 on June 5, even with 12 strikeouts in his first five innings, stopping a 20-game regular season winning streak and giving him his first loss in 11 months.

[87] Despite a career-low 6.2 strikeouts per nine innings (K/9), down from his 9.3 high in 2015, Arrieta posted an ERA of 0.90 in May 2018 by generating weak contact ground balls for easy outs.

"[89] After one game in which the Phillies lost 6–1 to the San Francisco Giants, Arrieta criticized his teammates for their poor defense, especially on infield shifts.

He targeted Scott Kingery in particular for not moving quickly enough on the ball that ultimately set up Andrew McCutchen for a three-run home run.

[44] Following the 2018 season, Arrieta revealed that he had injured his knee in June, and that he had chosen to pitch through the pain, hiding the injury from his teammates and from manager Gabe Kapler.

[92] After re-injuring his knee during an offseason workout, Arrieta discovered that he had suffered a meniscus tear, and he underwent surgery in January to repair the joint.

[96] On August 17, Arrieta and the Phillies announced that the pitcher would undergo a season-ending surgery to remove a bone spur in his pitching elbow.

[98] The COVID-19 pandemic, which shortened the 2020 MLB season to only 60 regular-season games, proved an added challenge for Arrieta, who was entering the final year of his contract with the Phillies.

[100] Two positive COVID-19 tests in the Phillies clubhouse shut the team down for one week, and Arrieta did not receive his first start of the season until August 3, his first MLB appearance in nearly one year.

[105] On June 4, he attempted to play through a bout of gastroenteritis and proceeded to allow six runs in two innings of an 8–5 loss to the San Francisco Giants.

[106] As the season progressed, Cubs management began to voice concerns about Arrieta's pitch command and durability: not once in his first 13 starts of the year did he remain on the mound past the fifth inning.

[109] Four days after his release from the Cubs, Arrieta signed a minor league contract with the San Diego Padres, whose starting rotation had been depleted by injuries to Chris Paddack and Yu Darvish.

[115] On April 18, 2022, Arrieta announced his retirement from professional baseball on the Barstool Sports podcast Pardon My Take, saying, "I haven't signed the papers, but I'm done ... At some point, the uniform goes to somebody else, and it's just my time.

[121] To combat this decreased velocity, Arrieta increased his use of breaking balls to confuse hitters while also relying on a sinking fastball to keep pitches low to the ground and playable for fielders.

[127] When the Cubs visited the White House to meet with then-President of the United States Barack Obama after their World Series victory in 2016, Arrieta clarified that his absence was not for political reasons, but due to the needs of his family.

In the "Baseball" episode of the HBO comedy series Veep, protagonist Selina Meyer meets several members of the Orioles, including Arrieta and teammate Tommy Hunter.