Mathieson made his MLB debut June 17, 2006, losing to the Tampa Bay Devil Rays, 7–2. Matheison suffered an elbow injury September 2 that required Tommy John surgery.
Mathieson began a rehabilitation program late in the 2007 season, but removed himself from a game August 31 while pitching for Double-A Reading when he felt "a strange sensation in his elbow."[2] The Phillies announced September 4 that Mathieson would not return during 2007 due to inflammation of the ulnar nerve.[3] Mathieson was scheduled to play in the 2007 Arizona Fall League with the Peoria Saguaros, but didn't.[4]
As of 2009, Mathieson was pitching for the GCL Phillies in his effort to return to the major leagues.[5]
On June 17, 2010, Mathieson was recalled from the Lehigh Valley IronPigs to the Philadelphia Phillies,[6] where he remained for several weeks. He also spent parts of the 2011 season with the club in addition to his time with Lehigh Valley.
In November 2011, Mathieson was released from the Phillies to pursue pitching opportunities in Asia.[7]
With the conclusion of the 2016 NPB season, his fifth year in Japan with the Yomiuri Giants, Mathieson had appeared in 300 games as a relief pitcher, compiling a 21–20 record with 2.32 ERA and 43 saves. He has 353 strikeouts and a 1.08 WHIP overall in NPB.
Mathieson announced the end of his professional playing career at the conclusion of the 2019 season.[9]