Arrieta won the NL Cy Young Award to become the first Cubs pitcher to do so since Greg Maddux in 1992. He was the fifth Cubs winner overall, also joining Fergie Jenkins (1971), Bruce Sutter (1979) and Rick Sutcliffe (1984). He also came in sixth in the voting for 2015 NL Most Valuable Player Award.

Arrieta attended Weatherford Junior College for his freshman year in 2005, posting a 6–2 win-loss record with a 3.43 ERA. Following his freshman year, Arrieta was selected by the Milwaukee Brewers in the 26th round of the 2005 Major League Baseball draft.

Instead, he opted to transfer to Texas Christian University (TCU), where he played for the TCU Horned Frogs baseball team for his sophomore and junior seasons, and studied sport psychology. During the summer of 2005, prior to enrolling at TCU, Arrieta participated in summer collegiate baseball with the McKinney Marshalls of the Texas Collegiate League, and posted a 4–3 record in 10 starts with a 1.87 ERA over 62 ⁄3 innings pitched. During his sophomore year in 2006, Arrieta led college baseball with 14 wins and had a 2.35 ERA over 19 appearances, and he had 111 strikeouts in 111 innings. He won the Mountain West Conference Pitcher of the Year Award and was named a Second-Team College Baseball All-American after his sophomore year.

Arrieta first joined the United States national baseball team in 2006, and helped the team win the World University Baseball Championship in Cuba. He was 4–0 with 34 strikeouts and a 0.27 ERA—allowing just one earned run in 35 innings pitched over six starts for the team. In his first start at the 2008 Summer Olympics in Beijing, Arrieta pitched six innings and struck out seven in Team USA’s 9–1 victory over the China national baseball team.

In 2007, his junior year, he was 9–3 with a 3.01 ERA. He was named First-team All-Mountain West in 2007.

Arrieta made his professional debut in the Arizona Fall League with the Phoenix Desert Dogs in 2007. He posted 16 scoreless innings, while striking out 16 over 14 appearances, and helped lead the Desert Dogs to the Arizona League championship.

Arrieta made his major league debut on June 10, 2010, against the New York Yankees at Camden Yards. He pitched six innings, giving up four hits and three runs, striking out six and earning the win. For the 2010 season, he was 6–6 with a 4.66 ERA in 100 ⁄3 innings.

He won the home opener for the Orioles in 2011, and was the youngest opening day starting pitcher for the Orioles since Mike Mussina in 1994. In 2011, he was 10–8 with a 5.05 ERA in 113 ⁄3 innings. Arrieta was again named the opening day starter for the Orioles in 2012. After starting the 2012 season 3–9 with an ERA of 6.13, Arrieta was demoted to Triple-A on July 6, 2012.

During the offseason, Arrieta lives in Austin, Texas, with his wife, Brittany, and their two children. He is known as a “workout freak” and uses cross-training in his workouts. Arrieta does pilates and incorporates kale juice, nuts, and fruits into his diet. Arrieta’s maternal grandfather is of Puerto Rican ancestry. Arrieta served as a groomsman for former TCU teammate Matt Carpenter’s wedding on December 10, 2011.

In 2012, Arrieta appeared in the HBO television show Veep, alongside Orioles teammate Tommy Hunter. In 2017, Arrieta appeared in an episode of Chicago Fire alongside Cubs teammate Kris Bryant.

Arrieta began the 2013 season with four starts for the Orioles posting a 1–1 record and a 6.63 ERA until being sent down to the Triple-A Norfolk Tides on April 22 after the Orioles recalled Alex Burnett. He was recalled by the Orioles on May 18 and later optioned back down to Triple-A to make room for Kevin Gausman on May 23. He was recalled again on June 14 and Gausman was optioned to Triple-A to make room on the roster for Arrieta. In 2013 with Baltimore, he was 1–2 with a 7.23 ERA in 23 ⁄3 innings. Through four years with the Orioles, Arrieta posted a record of 20–25 and a 5.46 ERA in 358 innings.

On July 2, 2013, the Orioles traded Arrieta along with Pedro Strop to the Chicago Cubs for Scott Feldman and Steve Clevenger. He was optioned to the Iowa Cubs of the Class AAA Pacific Coast League upon being acquired. After making 5 starts for Iowa, Arrieta was recalled to start Game 2 of a doubleheader against the Brewers on July 30. In his Chicago debut, he gave up 1 run in 6 innings, earning a no-decision in the 3–2 loss. After the game, Arrieta was optioned to Iowa where he made two more starts before being recalled on August 14 to replace Carlos Villanueva in the rotation. He made eight more starts before the end of the season. In his nine starts with Chicago, he went 4–2 with a 3.66 ERA, striking out 37 in 51 ⁄3 innings. In 30 games (29 starts) in 2013 including the minors, Arrieta went 12–9 with a 4.42 ERA, striking out 137 in 154 ⁄3 innings.

Arrieta took no-hitters into the seventh or eighth innings three times in the 2014 season. On June 24, Arrieta retired the first 18 Reds in order, but the perfect game was broken up by Cincinnati’s Billy Hamilton’s leadoff double in the seventh. On June 30, against the Red Sox, Arrieta took a no-hitter into the 8th until Stephen Drew singled with two outs the inning.

For the 2014 season, he posted a 10–5 record with a 2.53 ERA, and in 156 ⁄3 innings he gave up 114 hits, walked 41, and struck out 167. He came in 9th in voting for the National League Cy Young Award.

On July 12, 2015, Arrieta pitched a complete game victory over the Chicago White Sox at Wrigley Field, his second complete game of the season and the third of his major league career. On August 20, Arrieta became the first MLB pitcher to win 15 games in the 2015 season. Ten days later, Arrieta no-hit the Los Angeles Dodgers at Dodger Stadium for the 14th no-hitter in Cubs history. He struck out 12 batters, including all three batters he faced in both the first and ninth innings. 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. Arrieta was named the NL Player of the Week for August 24–30 and NL Pitcher of the Month for August with a 6–0 and a 0.43 ERA and the no-hitter. 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. On September 22, Arrieta won his 20th game of the season, throwing a three-hitter against the Brewers. With 11 more strikeouts in that 4–0 Cubs victory at Wrigley, he was the first MLB pitcher to win 20 games this season and had his fourth complete game and third shutout of the season.

After the 2015 All-Star break, he gave up 9 earned runs during 15 starts over 107 ⁄3 innings for a 0.75 ERA, the lowest in MLB history in the second half. On October 5, he was again named NL Pitcher of the Month for his 4–0 September record with a 0.45 ERA.

On February 5, 2016, Arrieta and the Cubs agreed on a record arbitration deal worth $10.7 million 2016 salary, the largest one-year contract for a second-time arbitration eligible pitcher, topping David Price’s $10.1 million salary in 2013. The club chose him as the 2016 season Opening Day starting pitcher against the Angels on April 4.

In 2016, he was 18–8 with a 3.10 ERA (10th in the NL) in 197 ⁄3 innings. He led the league for the second consecutive year with 6.294 hits per 9 innings pitched, his 18 wins were third in the league, his .692 win-loss percentage was sixth, his 1.084 walks plus hits per innings pitched and 0.730 home runs per 9 innings pitched were seventh, his 190 strikeouts and 197 ⁄3 innings pitched were eighth, and his 8.666 strikeouts per 9 innings pitched were tenth. He won a Silver Slugger Award after batting .262/.304/.415 with 2 home runs and 7 RBIs in 65 at bats, and came in ninth in voting for the 2016 NL Cy Young Award.

On January 13, 2017, he agreed to a contract for the 2017 baseball season. He was NL Pitcher of the Month in August.

In 2017, Arrieta made 30 starts with a 14–10 record and a 3.53 ERA (eighth in the National League) in 168 ⁄3 innings. He threw 14 wild pitches, tied for most in the National League, his 10 hit by pitch were 5th in the NL, and his 8.020 hits per 9 innings pitched and 1.218 walks plus hits per 9 innings pitched were tenth in the league. The Cubs finished the season 92–70 and clinched another NL Central division title.

Arrieta started Game four of the 2017 NLDS and, after 90 pitches, left in the fourth inning trailing 1–0. The Cubs and Arrieta lost that game to the Washington Nationals but won Game Five and moved on to the 2017 NLCS. After three losses and facing elimination, Arrieta was the starter and winning pitcher in a Game Four victory against the Dodgers. After the Cubs season ended in a Game Five loss to the Dodgers, Arrieta declined the Cubs’ $17.4 million qualifying offer and became a free agent for the first time in his career.

On March 11, 2018, Arrieta agreed to a three-year, $75 million contract with the Philadelphia Phillies. He tore cartilage in his left knee in June, but did not tell the front office and was 1-5 with a 6.35 ERA over his last nine starts. For the season, he was 10–11 with a 3.96 ERA in 172 ⁄3 innings. He was second in the league in wild pitches (11), second among NL pitchers in errors (4), and third in the NL in salary ($30 million). He had the highest ground ball percentage among National League pitchers (51.6%), and induced a career-high 22 ground ball double plays, tied for 6th-most in Major League Baseball. For the fourth consecutive season he made 30 or more starts, one of seven NL pitchers to do so in that time period. On defense, he had the lowest fielding percentage of all major league pitchers with 170 or more innings pitched, at .862. After the 2018 season concluded, he was sixth of all active pitchers in career hits per 9 innings pitched (7.551).

In January 2019, he had an MRI on his injured left knee and a surgical procedure to clean up the meniscus in his knee. On August 17 it was announced that Arrieta would have season-ending surgery to remove a bone spur in his right pitching elbow. In 2019 he was 8-8 with a 4.64 ERA, and 110 strikeouts in 135.2 innings.

Through 2019, Arrieta was 8th of all active pitchers in career hits-per-9-innings-pitched, at 7.767.