He played in Major League Baseball (MLB) for the Washington Nationals, Milwaukee Brewers, Toronto Blue Jays, and Oakland Athletics.

In 2005 with Long Beach State, Estrada pitched to an 8–3 win-loss record and 2.43 earned run average (ERA) in 18 appearances (17 starts).

He posted a record of 3 wins and 4 losses and a 3.98 ERA over 61 innings, consisting of 12 starts and 1 appearance in relief, striking out a total of 56 batters and walking 20.

Estrada began the 2008 season with the Harrisburg Senators of the Double-A Eastern League, where he pitched 74+1⁄3 innings in 13 starts, posting an ERA of 2.66, striking out 67 batters and walking 32.

He was recalled to the big league club and made his Brewers debut on May 18, entering the game against the Cincinnati Reds as a relief pitcher in the 5th inning.

Between being the long reliever and backup starter (starting in a total of seven games), Estrada pitched in 92.2 innings, posted a 4.08 ERA, and struck out 88 batters for an impressive 8.5 K/9.

He began the 2015 regular season in the bullpen, but was moved into the starting rotation after the Blue Jays optioned Daniel Norris to the Triple-A Buffalo Bisons on May 1.

[12] On October 11, Estrada made his first career postseason start, and held the Texas Rangers to 1 run over 61⁄3, earning the win as the Blue Jays avoided elimination.

[13] He started game 1 of the 2015 American League Championship Series, taking the loss as the Blue Jays were shut out by the Kansas City Royals, 5–0.

[14] Down 3–1 in the series, Estrada started game 5 for Toronto on Oct. 21 and held Kansas City to 1 run over 72⁄3, avoiding elimination for the second time in the 2015 postseason with a 7–1 victory.

[19] On December 17, the Toronto chapter of the Baseball Writers' Association of America voted Estrada the Blue Jays' Pitcher of the Year.

[21] He made his season debut on April 10, and pitched seven shutout innings against the Boston Red Sox, leading the Blue Jays to a 3–0 victory in his 100th career start.

[22] In a 7–2 victory against the Philadelphia Phillies on June 15, Estrada set a Blue Jays franchise record by allowing 5 or fewer hits in 10 consecutive starts.

[27] The following day, Jon Morosi of MLB Network tweeted Estrada had been pitching with a herniated disk in his back since the All-Star break.

[28] For the season, he was 9–9 with a 3.48 ERA, and again led the major leagues in holding opposing batters to the lowest batting average on balls in play (.234).

[30] In Game 1 of the 2016 ALDS against the Texas Rangers, Estrada came within two outs of a complete-game shutout, before an Elvis Andrus triple ended his outing.