In 2008, USA Today named Cole to their All-USA high school baseball team. Baseball America rated him the 17th-best prospect available in the 2008 Major League Baseball draft. He was named the ESPN Rise Athlete of the Month for three consecutive months in March, April, and May 2010. He was named the starting pitcher of the 2008 Orange County North–South All-Star Game.

John Savage, coach of the UCLA Bruins, made Cole the team’s Friday night starting pitcher in his freshman year. That season, Cole recorded a 4–8 win–loss record with a 3.49 ERA, collecting 104 strikeouts in 85 innings. Cole was a member of the 2009 United States collegiate national baseball team and was named to the 2010 Collegiate National Team roster. He competed in the 2010 World University Baseball Championship.

During UCLA’s 2010 season, Cole and Trevor Bauer contributed in making the Bruins the best baseball team (51–17 record) in school history and the second-best team in the country. Cole had an 11–4 win–loss record, a 3.37 ERA, and 153 strikeouts in 123 innings. His 153 strikeouts placed Cole third among collegiate pitchers. The Bruins went on to play in the 2010 College World Series, but were defeated by South Carolina in the NCAA Championship Series.

Cole’s statistics declined in 2011, his junior year. He finished the season with a 6–8 win-loss record and a 3.31 ERA, with 119 strikeouts in 114 ⁄3 innings.

Heading into the 2011 MLB draft, Cole, Bauer, and Danny Hultzen, also a college pitcher, were seen as among the best available talents in the draft. The Pittsburgh Pirates selected Cole with the first overall selection. He signed a minor league contract with an $8 million signing bonus, the highest signing bonus ever offered to a rookie, 15 minutes before the signing deadline on August 15, 2011. Though he signed too late to pitch in the 2011 minor league season, he pitched for the Mesa Solar Sox of the Arizona Fall League (AFL). He recorded 16 strikeouts in 15 innings pitched for the Solar Sox and had a 3.00 earned run average (ERA) and a 0.93 walks plus hits per inning pitched ratio (WHIP). He was selected to start the AFL Rising Stars game in November 2011.

The Pirates invited Cole to spring training in 2012 as a non-roster invitee, but they optioned him to the minor leagues. Cole started the 2012 season with the Bradenton Marauders of the Class A-Advanced Florida State League, along with fellow starting pitcher Jameson Taillon, the Pirates’ first selection in the 2010 MLB draft. Cole was named a FSL Mid-Season All-Star. He was promoted to the Altoona Curve of the Class AA Eastern League on June 15, 2012. He was named to appear in the 2012 All-Star Futures Game. In twelve starts with the Curve, Cole pitched to a 2.90 ERA, before the Pirates promoted him to the Indianapolis Indians of the Class AAA International League on August 29, 2012.

Due to injuries to James McDonald and Wandy Rodríguez, the Pirates promoted Cole to the major leagues, to make his MLB debut on June 11, 2013. During his debut, he struck out the first batter he faced, Gregor Blanco, on three pitches; the last one at 99 miles per hour (159 km/h). He also recorded his first career hit, a 2-run single with the bases loaded in his first career plate appearance. Cole pitched 6⅓ innings being charged with two earned runs but got the win as the Pirates won over the San Francisco Giants, 8–2. Cole became the fourth pitcher since 1920 to drive in 2+ runs and earn the win in his Major League debut. Cole is the first Pirate to start his career with wins in his first four starts since Nick Maddox in 1907. He was the fifth pitcher for any team to accomplish the feat in the past 40 years, joining Rich Gale of the 1978 Royals, Kaz Ishii of the 2002 Dodgers, Jered Weaver of the 2006 Angels and Scott Lewis of the 2008 Indians.

Cole was voted the National League (NL) Rookie of the Month for September 2013. On the month, Cole had a 4–0 record and led all rookies with a 1.69 ERA and 39 strikeouts. Cole had a 10–7 record and a 3.22 ERA in 19 starts for Pittsburgh in 2013. Cole started Game Two of the 2013 National League Division Series, going six innings allowing two hits, one earned run, and five strikeouts, and ultimately defeating the St. Louis Cardinals. The Pirates chose Cole to start the deciding Game 5 over A. J. Burnett. The Cardinals won the game, and the series.

After focusing on his fastball during his rookie season, Cole entered 2014 spring training working on improving his curveball and slider. Cole has been a durable pitcher in 2014 pitching 75 1/3 innings, but manager Clint Hurdle acknowledged on June 7 that Cole would miss at least one start with shoulder fatigue. Cole was placed on the 15-day disabled list the next day, and activated on June 28.

On September 7, 2014, Cole hit his first career home run at Wrigley Field off of Chicago Cubs pitcher Blake Parker. On September 23, Cole helped the Pirates clinch a second consecutive playoff berth by beating Alex Wood and the Atlanta Braves.

On June 14, 2016, Cole was placed on the 15-day disabled list due to a right triceps strain. On July 27, Cole pitched his first complete game against the Seattle Mariners. In 2017, Cole was 12–12 with a 4.26 ERA, as he led the National League with 33 starts.

The Pirates and Cole reached agreement in January 2018 on a one-year, $6.75 million contract.

On January 13, 2018, the Pirates traded Cole to the Houston Astros for Joe Musgrove, Michael Feliz, Colin Moran and Jason Martin.

On April 29, 2018, Cole struck out 12 hitters in a game against the Oakland Athletics that resulted in a no-decision but an Astros win. In doing so, Cole broke the Astros strikeout record for April with 61 strikeouts in the first month. He finished his first month in an Astros uniform going 2–1 with 61 strikeouts and a 1.73 ERA in 41.2 innings pitched. On May 4, against the Arizona Diamondbacks Cole struck out 16, allowed only one hit, and pitched his first career shutout as the Astros won 8–0.

On September 8, 2019, his 29th birthday, Cole became the second pitcher ever to strike out 14 or more hitters in three consecutive games. On September 18, 2019, Cole struck out his 300th batter of the season, becoming the third Astros pitcher to strike out 300 batters in a single season, after J. R. Richard and Mike Scott. Cole became the second-fastest pitcher to register 300 strikeouts in terms of innings pitched. His 198 ⁄3 innings trails only Randy Johnson, who achieved the feat in 197 ⁄3 innings in 2001. The following start, September 24, 2019, Cole struck out 14 batters to break the single-season strikeout record for any Astros pitcher, bringing his total to 316 on the year, and allowing only two singles in his appearance of seven scoreless innings. In his next start on September 29, 2019, Cole set an MLB record with his ninth consecutive outings with at least 10 strikeouts.

On December 18, 2019, Cole signed a nine-year contract worth $324 million with the Yankees. Cole’s contract is the largest signed by a pitcher, topping the $245 million, seven-year contract signed by Stephen Strasburg. Cole’s contract has an average annual value of $36 million, which also represents the highest average annual value of any player contract in Major League Baseball, eclipsing the previous average annual value record set by Mike Trout, at an average annual value of $35.5 million. The contract also allows Cole to opt out and become a free agent again after the fifth year; however, if he attempts to do so, the Yankees can choose to prevent him from doing so by adding an additional year and $36 million to his contract, which would bring the total length and value of the contract to 10 years and $360 million.

Cole attended the 2001 World Series, of which the Yankees took part. He held a sign that said “YANKEE FAN TODAY TOMORROW FOREVER”, and a photograph shared by Newsday went viral in 2019 when news of his signing with the Yankees was reported. He brought the sign to his introductory press conference with the Yankees.

On July 23, 2020, Cole made his Yankees debut as a Opening Day starting pitcher throwing 5 innings against the Washington Nationals and allowing just one hit, a home run by Adam Eaton. Cole’s regular-season winning streak reached 20, the third-longest in MLB history, but his streak ended on August 26, 2020 when he took a loss against the Atlanta Braves. He would lose three decisions in a row, but on September 11, 2020, Cole ended his 3-game losing streak by throwing a 2-hitter complete game shutout against the Baltimore Orioles. As it was a doubleheader, the game only went 7 innings. He ended his first season as a Yankee with a 7–3 record, throwing to a 2.84 ERA in 73 innings and striking out 94.

On September 29, 2020, in his Yankees playoff debut, during Game 1 of the wild card game against the Cleveland Indians, Cole struck out 13 batters without a walk, tying Tom Seaver (1973 NLCS Game 1) and second most in Yankees franchise history. He also became the first Major Leaguer in history to win three postseason games with 12 or more strikeouts. Only Roger Clemens (15 K’s) has fanned more in a postseason start with the Yankees.

Cole is married to Amy Crawford, a former UCLA softball player and the sister of San Francisco Giants shortstop Brandon Crawford. They met when they attended UCLA. On January 1, 2020, Amy announced their first pregnancy. Their son, Caden Gerrit Cole, was born on June 30th, 2020.