He played in Major League Baseball (MLB) for the Detroit Tigers, Florida Marlins, Boston Red Sox, Baltimore Orioles, New York Yankees, Cleveland Indians, and St. Louis Cardinals.

Primarily a starting pitcher who struggled early in his MLB career, Miller found sustained success as a reliever utilizing a multi-faceted fastball and slider approach that proved deceptive for batters to hit.

[2] After graduating from Buchholz, Miller attended the University of North Carolina (UNC) at Chapel Hill and majored in Business Administration.

[2] As a freshman in 2004, Miller made his college debut as a starting pitcher versus Gardner–Webb on February 25, recording six shutout innings pitched.

[2] In 16 starts, Miller totaled 96+2⁄3 innings and posted an 8–4 record, 2.98 ERA, 104 strikeouts, .230 BAA, 9.68 K/9, 52 bases on balls and 19 hit batters.

[2] As the Tar Heels' third starter on February 19, 2006, against Seton Hall, Miller logged six shutout innings with nine strikeouts, including reaching 200 for his career.

He also struck out 11 Eagle batters to set the school career strikeout record and earned ACC Pitcher of the Week honors on May 22 for the third time of the season.

[2] On January 30, 2016, UNC commemorated Miller's accomplishments during the half-time of a men's basketball game versus Boston College and retired his uniform number 33.

[13][14] In a July 2004 game versus the Falmouth Commodores called by fog after four innings, he struck out 12 batters, including future Red Sox teammate Jacoby Ellsbury.

That year, he also won the Robert A. McNeece Award (outstanding professional prospect) and was a co-winner with Tim Norton of Falmouth and Uconn for the B.F.C.

[22] While Miller did not make the Tigers' opening day roster in 2007, he made his first major league start May 18, 2007, versus the Cardinals.

Starting in place of the injured Jeremy Bonderman, he completed six scoreless innings with four hits, three walks and two strikeouts, earning his first major league victory.

His best game pitched of 2007 was a six-inning performance in Atlanta on June 24, allowing four hits and no runs while also striking out two batters and walking two ending in a 5–0 Tigers victory.

[22] On December 5, 2007, the Tigers traded Andrew, Cameron Maybin, Mike Rabelo, Dallas Trahern, Eulogio de la Cruz and Burke Badenhop to the Florida Marlins for Dontrelle Willis and Miguel Cabrera.

[22] During spring training in 2010, the Marlins announced that they would assign Miller to their Triple-A minor league team, New Orleans to open the season.

Manager Terry Francona estimated that he "must have made 15 calls that winter trying to get him to come to the Red Sox" after the club non-tendered him because he saw that flaws in his pitching mechanics could be easily corrected.

[26] During 2011 spring training, Boston optioned Miller to minor league camp and announced that he would begin the year as a starting pitcher with the Triple-A Pawtucket Red Sox.

He was especially effective at home at Fenway Park, stranding 24 of 26 inherited runners (92.3%) and allowing one run in 26 games for a 0.39 ERA in 23 IP while limiting opponents to a .105 batting average and career-low .229 on-base percentage.

[41] Before the season started, Yankees manager Joe Girardi announced that Miller and Dellin Betances would split the closing job.

[50] Prior to the 2016 season, the Yankees informed Miller that he would serve as the eighth-inning setup man[51] with the acquisition of Aroldis Chapman, considered one of baseball's top closers.

[52] However, early in spring training, MLB suspended Chapman for 30 games to commence with the start of the upcoming regular season, and the Yankees temporarily reinstalled Miller as closer.

On July 31, 2016, the Yankees traded Miller to the Cleveland Indians for Clint Frazier, Justus Sheffield, Ben Heller and J. P.

The Indians swept Boston in the ALDS and Miller completed four innings in two appearances, permitting two hits, walking two and striking out seven.

[64] He played in two innings each of Games 1 and 2 in the American League Championship Series (ALCS) against the Toronto Blue Jays, striking out ten of 12 batters faced.

He was named ALCS Most Valuable Player (MVP), having completed 7+2⁄3 scoreless innings, allowing three hits, no walks and striking out 14.

[71] Dexter Fowler homered off Miller in Game 4, ending his scoreless streak at 17 innings in the 2016 playoffs and 24+1⁄3 to commence his postseason career.

[74] In spite of finally succumbing in pivotal Game 7 to the Cubs' offense, Miller was named the 2016 Esurance MLB/This Year in Baseball Award winner for Best Postseason Major Leaguer.

[78] The Indians reactivated Miller on September 14, the day they broke the American League record for longest winning streak at 21 games.

[87] Miller earned the first major international championship of his baseball career when Team USA defeated Puerto Rico 8−0 in the final on March 22, 2017.

[91][92] Both attempting to lead sequences against hitters with the fastball and a myriad of mechanical issues limited Miller's success as a starting pitcher early in his major league career.