Following his high school career, Mattingly accepted a scholarship to play baseball for the Indiana State Sycamores. His father, Bill, informed Major League Baseball (MLB) teams that his son intended to honor that commitment and would not sign a professional contract. Mattingly lasted in the 1979 Major League Baseball draft until the 19th round, when he was selected by the New York Yankees. He was not interested in attending college, so he chose to sign with the Yankees, receiving a $23,000 signing bonus.
Mattingly began his professional career in Minor League Baseball with the Oneonta Yankees of the Class A-Short Season New York–Penn League in 1979. He hoped to bat .500 for Oneonta and was disappointed with his .349 batting average, which never went lower than .340. He batted a league-leading .358 in 1980 for the Greensboro Hornets of the Class A South Atlantic League in addition to recording a league-best 177 hits. He won the league MVP award and was named to the postseason All-Star team. With the Double-A Nashville Sounds in 1981, he hit .316 and led the Southern League with 35 doubles. He was selected to play in the Southern League All-Star Game and named to its postseason All-Star team.
Mattingly married Kim Sexton on September 8, 1979; they are now divorced. They have sons: Taylor, Preston, and Jordon. Taylor was drafted in the 42nd round (1,262nd overall) of the 2003 Major League Baseball draft by the New York Yankees, and played in 24 games for the Gulf Coast Yankees in the rookie league before an injury cut short his season. After sitting out all of 2004 and 2005, Taylor retired from baseball in 2005 after only 58 professional at bats. Of his eldest son, Don observed: "He loved the game, not the lifestyle."