He made his first major league appearance on May 17, 2005, against the Cleveland Indians, in which he gave up the pitching version of the cycle in first four batters that he faced.

In the pivotal Game 5 of the American League Division Series of the playoffs against the New York Yankees, Angels ace Bartolo Colón went out with a shoulder injury in the second inning.

Pitching in the 2008 MLB All-Star Game, Santana gave up a fifth inning homer to Matt Holliday of the Colorado Rockies.

On September 22, 2008, Santana pitched against the Seattle Mariners, going 8 innings, allowing 5 hits, 1 earned run, and striking out 9 en route to his career-high tying 16th win of the season.

He finished the season with a career-high 214 strikeouts, good for second in the American League behind A. J. Burnett, while pitching to a 3.49 ERA in 219 innings across 32 starts.

On October 31, 2012, Santana was traded to the Kansas City Royals in exchange for left-handed minor league reliever Brandon Sisk.

The Angels picked up the $13 million option on Santana prior to making the trade, and agreed to cover an undisclosed portion of that amount for the Royals.

As a result of that and some concerns about his long term health and his reported contract demands, Santana did not sign with any teams before spring training began.

[5] As spring training continued, Santana fired his agent and changed his contract demands to a one-year deal near what his rejected qualifying offer was.

[6] Santana proceeded to negotiate with the Toronto Blue Jays, and verbally agreed to a contract but stalled signing it for several days.

[7][8] Following an injury to Kris Medlen of the Atlanta Braves, Santana immediately agreed to terms identical to the Blue Jays' reported offer of $14.1 million for one season.

[10] On April 3, MLB announced that Santana would be suspended for 80 games after testing positive for Stanozolol, a performance-enhancing drug.

[11] On July 5, 2015, Santana was activated from his 80-game suspension and made his season debut against his former team, the Kansas City Royals.

Despite a 7–11 record, largely due to poor run support, Santana finished with a strong 3.38 ERA in 181 innings pitched (30 starts).

[14] On April 15 Santana pitched a complete game one hit shutout against the White Sox, he struck out eight and walked one batter.

Santana became the first pitcher in the American League to record three complete-game shutouts in a season since Rick Porcello in 2014, and the first to do so prior to the All-Star break since Justin Masterson in 2013.

At that time Santana had a 10–5 record with a 3.07 ERA in 111+1⁄3 innings, while limiting opponents to a .204 batting average, second in the American League behind Chris Sale.

He finished the season 16–8 with a 3.28 ERA and 1.13 WHIP in 211+1⁄3 innings, notching 167 strikeouts against 61 walks, while pacing the lead in the Major Leagues with 5 complete games (3 shutouts).