He played in Major League Baseball (MLB) for the New York Yankees, Washington Nationals, Oakland Athletics, New York Mets, Arizona Diamondbacks, Chicago White Sox, Houston Astros, Toronto Blue Jays, Cleveland Indians, and Minnesota Twins.

[9] After taking classes at Dunedin for a month, Clippard transferred back to Mitchell in order to graduate from high school with his friends.

He earned pitcher of the week honors in the Florida State Elite Baseball League in June 2003.

[7] He trained with Roy Silver, a retired professional baseball player, who worked with Clippard on his mechanics and his maturity.

Though he had signed a National Letter of Intent in the fall of 2002 to attend the University of South Florida on a baseball scholarship, allowing him to play college baseball for the South Florida Bulls,[18] he chose to turn professional due to his draft position and the opportunity to play for the Yankees.

Moving up to the Battle Creek Yankees of the Class A Midwest League for the 2004 season,[20] Clippard had a 10–10 record with a 3.44 ERA and a strikeout-to-walk ratio of 4.53:1 in 25 starts.

[22] However, he did not appear in the game, as the Charleston RiverDogs of the Class A South Atlantic League needed another pitcher that day.

He led Yankees farmhands in strikeouts and finished fifth in the affiliated minor leagues, behind Francisco Liriano, Joel Zumaya, Rich Hill and Chuck James.

However, he did not make the FSL post-season All-Star team[24] and Baseball America did not rank him as one of the league's top prospects.

[25] Baseball America ranked Clippard as the Yankees' tenth best prospect heading into the 2006 season.

[26] Promoted to the Trenton Thunder of the Class AA Eastern League in 2006, Clippard again led Yankee farmhands in strikeouts (175).

[28] Clippard also won nine straight games at one point, breaking the club record of eight shared by Tomo Ohka and Carl Pavano.

[29] Clippard again was fifth in the affiliated minors in strikeouts, trailing Yovani Gallardo, Francisco Cruceta, Matt Maloney and Franklin Morales.

Though the Yankees experienced injuries in the starting rotation, they called on Matt DeSalvo and Chase Wright before Clippard.

He became the seventh rookie to start a game for the 2007 New York Yankees, following Hughes, DeSalvo, Rasner, Wright, Kei Igawa and Jeff Karstens.

He recorded his first career hit in his second at-bat off Mets pitcher Scott Schoeneweis, a double to right center in the sixth inning.

[36] Though he was a member of the Trenton team as they won the Eastern League championship, Clippard struggled in the playoffs.

[47] During spring training in 2009, the Nationals optioned Clippard to the Syracuse Chiefs, Washington's new Class AAA affiliate.

[17] Clippard at first resisted the transition to the bullpen, but conversations with his father and agent, Casey Close, reassured him to continue pursuing his dream.

[58][60] Adrián Beltré, the only batter Clippard faced, singled, but Hunter Pence threw out José Bautista at home plate, and the NL took the lead in the next inning.

[62] Before the 2012 season, Clippard and the Nationals agreed to a one-year contract worth $1.65 million, avoiding salary arbitration.

After injuries to Storen and Brad Lidge, Henry Rodríguez became the closer, but Rodriguez lost the job to Clippard due to his struggles.

[73] On July 27, 2015, the Athletics traded Clippard to the New York Mets for pitching prospect Casey Meisner.

[86] On July 18, 2017, the Yankees traded Clippard, Blake Rutherford, Ian Clarkin, and Tito Polo to the Chicago White Sox for David Robertson, Todd Frazier, and Tommy Kahnle.

[86] On August 13, 2017, The White Sox traded Clippard to the Houston Astros in exchange for a player to be named later or cash considerations.

[90] After Roberto Osuna, the Blue Jays' closer, was placed on administrative leave in May, Clippard began receiving save opportunities.

[91] Clippard received his World Series ring on June 25, when the Blue Jays visited Houston.

[99] With the 2020 Minnesota Twins, Clippard appeared in 26 games, compiling a 2–1 record with 2.77 ERA and 26 strikeouts in 26 innings pitched.

[100] On February 22, 2021, Clippard agreed to a one-year, $2.25 million contract with the Arizona Diamondbacks that included a mutual option for the 2022 season.

[106] Two days later Clippard cleared waivers, refused an outright assignment, and elected for free agency according to a team announcement.