Santana won the pitching Major League Triple Crown, the first pitcher to do so since Dwight Gooden in 1985. He completed the season leading the majors in ERA (2.77) and strikeouts (245), and tied Chien-Ming Wang in wins (19). He became the first pitcher to win the triple crown with fewer than 20 wins, and the first to win it with an ERA above 2.60.

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. This was the first no-hitter in Mets franchise history, coming in their 51st season and 8,020th regular season game. 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. Santana walked five batters, recorded eight strikeouts, and lowered his season ERA to 2.38. He also threw a career-high 134 pitches, and earned the new nickname “No-han”. Notable moments in the game included a liner in the sixth inning by former Met Carlos Beltrán, which hit the foul line behind third base but was ruled foul. In the seventh inning, Mike Baxter made a difficult catch in left field, preserving the no-hitter, and then violently crashed into the wall. He left the game with a bruised left shoulder and was subsequently placed on the DL.

Santana was discovered in 1994 by Andres Reiner, who was a scout working for the Houston Astros at the time. Santana’s parents agreed to let him attend Houston’s academy in Valencia. When Astros scouting director Dan O’Brien called Reiner and asked if he had signed Santana to a contract, Reiner reported that he was still deciding if Santana was a better prospect as an outfielder or a pitcher. After six weeks of training, Santana was told he was going to pitch. Santana did not like it and almost left, but Reiner convinced him to stay. While originally a center fielder, Santana was converted to a pitcher at the academy due to his arm speed. In 1999 he was named the Tovar Mérida Athlete of the Year.

After the 1999 major league season, Santana was left unprotected by the Houston Astros and eligible in the Rule 5 draft. The Minnesota Twins had the first pick that year, the Florida Marlins had the second. The Twins made a deal with the Marlins: the Twins would draft Jared Camp with their first pick and the Marlins would draft Santana. The teams would exchange the two players with the Twins receiving $50,000 to cover their pick.

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 put up a 6.49 ERA in 86 innings pitched in 2000, his rookie year.

In 2002, the Twins sent Santana to the minors for 2 months to work almost exclusively on perfecting his changeup. He did this for 10 starts and came back up to the majors with a terrific changeup to complement his very good fastball. While in the minors, pitching coach Bobby Cuellar made Santana throw at least one changeup to every batter. According to Cuellar, Santana would sometimes throw 20 in a row during games.

Santana was used as a long reliever early in his career after finding little success as a starter. In 2002, he led the majors in wild pitches, with 15.

In 2003, Santana transitioned from relief to the Twins’ starting rotation after spending the first four months of the season in the bullpen. He won his last eight decisions and pitched the ALDS opening game against the Yankees.

Due to Santana’s early major-league success with the Twins, a young minor-league pitcher in the Anaheim Angels’ farm system also named Johan Santana changed his name to Ervin Santana in 2003 and has also achieved major league success. Santana underwent minor elbow surgery following the season.

In 2004, Santana enjoyed one of the great second halves of modern times. 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.

From 2004 to 2006, Santana led the league in strikeouts all three years, in ERA twice, and also led in several other key statistical areas. In this three-year span, he compiled a 55–19 record with an ERA of 2.75 and WHIP of 0.96, while striking out 748 batters.

Santana also led the AL in WHIP (1.00), opposing batting average (.216), and innings pitched (233.2). 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. A brief slump cost him the opportunity to make his 20th win of the season. No pitcher in Major League Baseball won 20 games in the 2006 season, the first time in modern major league history this occurred.

Santana won his second Cy Young Award in 2006, becoming the 14th player in MLB history to win the award multiple times. He became the fifth pitcher to win the award by a unanimous vote multiple times, joining Roger Clemens, Pedro Martínez, Greg Maddux and Sandy Koufax, who accomplished the feat three times.

In 2006, he started The Johan Santana Foundation to provide assistance to hospitals and bought new gloves and bats for children in surrounding areas. Also in 2006, Santana, as well as the Minnesota Twins, purchased a yellow firetruck for Tovar’s fire department. Santana has held a party the past two offseasons called El Cy Youngazo (the Great Cy Young) which includes a toy drive, musical groups, and beer from Santana’s sponsor, Regional. Proceeds from Johan’s charity wine, Santana’s Select, also support his foundation in entirety. In 2012, the Johan Santana Foundation expanded their efforts to reach the Hispanic community of New York by contributing to Tuesday’s Children, an organization that has made a commitment to families impacted by 9/11, First Responders and their families, and most recently, individuals who have lost loved ones to terrorism around the world. Johan contributed $10,000, matched with $10,000 by the Mets through the New York Mets Foundation, to expand Tuesday’s Children programming to include more resources for Spanish-speaking individuals and families impacted by 9/11.

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 July 1, 2007, Santana was named as a member of the 2007 All-Star Game, his third straight appearance. 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. The Twins won, 9–0, and Santana went the distance on a four-hitter. Santana shaved Blyleven’s head the following day. Santana had perhaps his best career game on August 19 against the Texas Rangers in which he struck out 17 batters over eight innings. He walked none and allowed only two hits, both to Sammy Sosa. His 17 strikeouts set a Twins club record for strikeouts in a game. Santana’s game score of 95 is the highest by any pitcher in MLB history in a non-complete game.

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. The Mets and Santana agreed to a six-year, $137.5 million contract. Santana was named the Opening Day starter, throwing 100 pitches in seven innings to earn the win against the Florida Marlins. On May 10, 2008, he earned his first win at Shea Stadium as a member of the New York Mets.

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 July 27, the day after the Mets played a 14-inning game where every pitcher in the bullpen was used, Johan pitched a complete game, striking out five and getting his first RBI as a Met against the St. Louis Cardinals, improving his record to 9–7. 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 23, Santana threw 125 pitches, a career-high to that point, in eight innings to beat the Chicago Cubs. 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.

On April 7, 2009, Johan Santana started the first game for the New York Mets in the 2009 season against the Cincinnati Reds. He went 5.2 innings allowing only one earned run, going on to win. In his second start on April 12 against the Florida Marlins Santana struck out 13 batters and surrendered two unearned runs over seven innings 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. Santana finished the season at a record of 13–9 with a 3.13 ERA.

In 2009, he was named # 3 on the Sporting News’ list of the 50 greatest current players in baseball. A panel of 100 baseball people, many of them members of the Baseball Hall of Fame and winners of major baseball awards, was polled to arrive at the list.

In a start on May 2, 2010 against Philadelphia, Santana gave up 10 runs in 3⁄3 innings, the worst start in his MLB career, surpassing his previous worst start on June 14, 2009 versus the Yankees, where he allowed nine runs and nine hits in just three innings. However, in the next five starts after that, Santana gave up only seven earned runs, striking out 21 and improving his record to 4–2 with a 3.03 ERA. Santana hit his first major league home run off of Matt Maloney of the Cincinnati Reds on July 6, finishing the game with a complete game shutout. From July 1 – 23, Santana was 3–0 with a 0.71 ERA in five starts. Santana, who was struggling to keep his 10–9 record through September 2, strained his pectoral muscle in a 65 pitch start versus Atlanta, for the second time in his career. His last game of the season was a win against the Atlanta Braves on September 2. On September 14, he underwent surgery to repair a torn anterior capsule in his left shoulder. Santana ended his season with a record of 11–9 and an ERA of 2.98. This was the third consecutive year that Johan had gotten injured.

On April 5, 2012, Santana was tabbed as the Mets Opening Day starter. This marked the first time Santana pitched in the majors since September 2, 2010 when he tore the anterior capsule in his left shoulder. He went five scoreless innings against the Atlanta Braves, striking out five batters. On May 26, Santana pitched a complete game shut-out against the San Diego Padres, the ninth of his career. He struck out seven over nine innings and improved to 2–2 with a 2.75 ERA over his first 10 starts. Then on June 1, Santana pitched a no-hitter against Adam Wainwright and the 2011 World Champion St. Louis Cardinals. After a few starts on July 21, Santana was placed on the 15-day disabled list by the Mets after spraining his right ankle. Santana was again put on the 15-day disabled list with inflammation in his lower back on August 22. He did not pitch for the remainder of the 2012 season. Santana finished the season 6–9 with a 4.85 ERA and 111 strikeouts in 21 starts and 117 innings pitched.

Santana tore his shoulder capsule for the second time during early 2013. Surgery was performed on April 3, 2013, by Dr. David Altchek. He missed the entire 2013 season amid questions about if his career would continue.

On November 1, 2013, the Mets bought out his 2014 option, paying Santana a $5.5 million buyout to avoid being responsible for a $25 million option for 2014, making Santana a free agent.

On March 4, 2014, he signed a minor league contract with the Baltimore Orioles, that included an invitation to Major League spring training. He would earn $3 million if he were to make the Major League roster. On June 2, the Orioles selected Santana’s contract from the Triple-A Norfolk Tides and placed him on the disabled list. On June 6, Santana tore his Achilles tendon during an extended spring training start and missed the rest of the 2014 MLB season. He became a free agent after the conclusion of the season.

Santana’s pitch repertoire included an 88–94 mph fastball along with a circle changeup, which was generally considered his best pitch, and a slider. It was reported on February 25, 2014, that Santana’s fastball velocity had dropped to 77–81 mph after his second left shoulder capsule surgery.

On February 26, 2015, Santana signed a minor league contract with the Toronto Blue Jays. The contract would have paid him $2.5 million if he made the 25-man roster, and included bonuses for active days and games started. He started the season on the disabled list of the Triple-A Buffalo Bisons, while rehabbing the shoulder muscles in his throwing arm. On April 23, it was reported that Santana planned on staying with the Blue Jays organization past his April 28 opt-out. 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.

Santana began the 2016 season as a free agent. In April, MLB Network’s Jon Heyman tweeted that Santana was eyeing a “mid-year comeback”. On May 11, 2016, his agent, Peter Greenberg, stated in an interview with Venezuelan radio show Los Cronistas that his client would aim to pitch in the majors during the second half of the season. If that didn’t work out, Greenberg said, Santana would pitch in the Venezuelan Professional Baseball League.

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