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 17. 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.