A two-time Cy Young Award winner with the Twins, Santana is a four-time All-Star and earned a pitching triple crown in 2006.

[3] Santana made his Major League debut with the Twins on April 3, 2000, coming from the bullpen vs. Tampa Bay.

He made his first MLB start on April 7, 2000, at Kansas City and recorded his first Major League win in a relief appearance at Houston on June 6.

He became the first pitcher since 1961 to give up four or fewer hits in 10 straight starts, and his 13–0 record broke the old Major League second-half mark shared between Burt Hooton and Rick Sutcliffe.

In addition, Santana set a team season record with 265 strikeouts, surpassing the old 258 mark registered by Bert Blyleven in 1973.

Santana struggled in his first outing of 2005, giving up four runs in the first inning, but quickly regained his composure and returned to Cy Young-winning form in an 8–4 victory over the Seattle Mariners.

However, the weak Twins club of the 2005 season cost him several otherwise-winnable games, and his winning percentage fell considerably in his second full year as a starter.

He continued to add to his reputation as a great second-half pitcher, losing only one game after the All-Star break while winning 10 and posting a 2.54 ERA.

After a slow start, with his record falling to 6–6 at one point, Santana jump-started his season with a four-hit shutout, followed by two wins.

On June 19, 2007, on the team bus to a game at Shea Stadium, Bert Blyleven said he would have his head shaved if that night's starting pitcher, Santana, threw a complete-game shutout.

[12] On February 2, 2008, Santana was traded from the Twins to the New York Mets for Carlos Gómez, Philip Humber, Deolis Guerra, and Kevin Mulvey.

[14] Santana was named the Opening Day starter, throwing 100 pitches in seven innings to earn the win against the Florida Marlins.

On June 1, 2008, Santana earned his 100th career victory, going 7.2 innings and allowing one run in a 6–1 win over the Los Angeles Dodgers.

On August 17, 2008, Santana pitched his second complete game for his 11th win of the season, allowing only three hits while walking none and striking out 7 in a 3–0 Mets shutout over the Pittsburgh Pirates.

On September 27, in the thick of a playoff race and on the final weekend of the season, Santana pitched a complete three-hit gem in a 2–0 win against the Florida Marlins on three days' rest.

It was later revealed that Santana had pitched that day, and perhaps in many other starts, with a torn meniscus in his left knee, for which he underwent successful surgery on October 1, 2008.

[16] Santana finished in third place in the NL Cy Young Award race behind Brandon Webb and winner Tim Lincecum.

In his second start on April 12, Santana struck out 13 batters and surrendered two unearned runs over seven innings against the Florida Marlins only to lose for the first time since June 28, 2008, against the New York Yankees.

On August 25 Santana was placed on the 15-day disabled list and missed the remainder of the season after having to undergo season-ending arthroscopic surgery to remove bone chips in his left elbow.

[17] In 2009, he was ranked number 3 on the Sporting News' list of the 50 greatest current players in baseball, behind Albert Pujols and Alex Rodriguez.

Santana, who was struggling to keep his 10–9 record through September 2, strained his pectoral muscle in a 65 pitch start versus Atlanta,[20] for the second time in his career.

Johan Santana missed the entire 2011 major league season while he recovered from anterior capsule surgery to his left shoulder (dominant), pitching only in the minors.

This marked the first time Santana pitched in the majors since September 2, 2010, when he tore the anterior capsule in his left shoulder.

[27] On June 1, in only the 11th start since returning from shoulder surgery, Santana threw a no-hitter against the St. Louis Cardinals, the defending World Series champions.

It marked only the eighth no-hitter in MLB history against a defending World Series champion team, the first since former Met Nolan Ryan blanked the Oakland Athletics in 1990.

In the seventh inning, Mike Baxter made a difficult catch in left field, preserving the no-hitter, and then violently crashed into the wall.

[44] Santana started the season on the disabled list of the Triple-A Buffalo Bisons while rehabbing the shoulder muscles in his throwing arm.

[45] On June 27, Santana announced that he was ending his 2015 season due to a toe infection and planned to resume his comeback in 2016.

In 2012, the foundation contributed to Tuesday's Children, an organization that helps families impacted by 9/11 and individuals who have lost loved ones to terrorism around the world.

[54] Santana was elected to the Twins Hall of Fame in 2018 with a pregame ceremony held at Target Field on August 4.