Drafted fourth overall by the Baltimore Orioles in the 2008 Major League Baseball Draft. Matusz signed a contract with the Orioles on August 15, 2008, the deadline to sign draft picks.
In spring 2009. he was invited to the Orioles spring training. In June 2009, he was promoted from high Single-A (Frederick Keys) to a starting pitcher for the Double-A Bowie Baysox. He struck out 10 batters in his first start for Bowie on June 17th. Matusz was named Baseball America's ninth best overall prospect mid-season in 2009. Before the 2010 season, Baseball America named him the fifth best prospect in all of baseball.
Matusz made his major league debut on August 4, 2009, against the Detroit Tigers. On his debut Matusz went five innings, allowing six hits, one earned run and striking out five. He earned a win in his effort. On September 14th, the O's decided to shut Matusz down for the remainder of the season, wary of overextending the rookie in his first big league season.
He was named a starting pitcher on Baseball America's 2010 All-Rookie Team.
He missed the first two months of the 2011 season with an injury. He returned and got six starts and finished with a 1-4 record with an ERA above 7.00 before being demoted to Triple-A Norfolk on July 1st to work on his velocity.
Matusz began the 2012 season in the rotation, but was demoted to the bullpen in August. In the bullpen, Matusz excelled, striking out 19 with a 1.35 ERA in 18 appearances. He also did not allow a single inherited runner to score. He pitched the last three months of the season with a rectus abdominis tear, preventing him from sprinting, but not pitching. He had surgery in October to repair the tear, and was expected to be back for spring training.