He grew up in Evansville, Indiana and was one of the nation's top prospects as a high school player at Reitz Memorial High School in 1979, even earning a brief write-up in Sports Illustrated magazine. However, most Major League Baseball teams were sure he was going to college, and didn't draft him. The Yankees took a chance, and were able to sign Mattingly after selecting him in the 19th round of the 1979 amateur draft.

The sweet-swinging lefty immediately proved it was a wise decision, terrorizing opposing pitchers. He batted .349 in 1979, .358 in 1980, .316 in 1981 and made it to the majors late in the 1982 season after batting .315 for Triple-A Columbus. Slugger Steve Balboni was the favored organizational prospect at first base, but it became apparent in 1982-1983 that Balboni was too prone to striking out and that his right-handed swing was not built for Yankee Stadium. Mattingly quickly surpassed Balboni, who was traded to the Kansas City Royals in 1984.

Don Mattingly spent his official rookie season of 1983 as a part-time first baseman and outfielder, waiting for a full-time spot in the lineup to open up. Mattingly wore number 46 during his rookie season. He played well, hitting .283, but with little power.

That part of his game arrived in 1984, when he became the Yankees' full time first baseman, switched his uniform number to 23, and was an MVP candidate. He hit .343 and beat out teammate Dave Winfield for the American League batting title by getting 4 hits in 5 at-bats on the last day of the season, which also gave him a league-leading 207 hits. He also slugged a league-leading 44 doubles to go with 23 home runs and 110 RBI.

He followed that up with a spectacular 1985 season, winning the MVP award in the American League; he batted .324 with 35 home runs, 48 doubles and 145 RBI, then the most RBI in a season by a major league batter since Ted Williams hit 159 in 1949. He may have been even better in 1986, when he led the league with 238 hits and led the league for the third straight year in doubles with 53. He also batted .352, hit 31 home runs and drove in 113 runs. However, he was beat out in the American League MVP voting by pitcher Roger Clemens, who also won the Cy Young Award that year. (It is somewhat controversial and rare for a pitcher to win the MVP award, with position players often winning the award even when a pitcher has a stand-out spectacular season.)

In 1987, Mattingly tied a major league record by hitting home runs in eight consecutive games and set an American League record by getting an extra base hit in ten consecutive games. Also in 1987, he set a major league record by hitting six grand slam home runs in a season. (Curiously, the six grand slams in 1987 were the only grand slams he hit in his entire career.) In June 1987, Mattingly injured his back during some clubhouse horseplay with pitcher Shane Rawley. Prior to this injury, Mattingly was a 162-game player. Though Mattingly would recover, his back would prevent him from ever putting up numbers like he did from 1984-1986. Nevertheless, he finished with a .327 batting average, 30 homeruns and 115 RBIs, his fourth straight year with at least 110 RBIs.

One of the most amazing statistics about Mattingly was how rarely he struck out, with his seasonal strikeouts barely exceeding his homeruns from 1984-1987 (33, 41, 35, and 38).

Mattingly remained among the game's best first basemen throughout the 1980s, winning the Gold Glove Award for his fielding and a spot on the American League All-Star team each year in the mid- to late 1980s. As late as 1989, he seemed to be on pace to shatter several career hitting records.

Mattingly's career came crashing down in 1990, when he again began to suffer from severe back problems. He tried to play through it, but struggled with the bat and had to go on the disabled list in July. He came back late in the season but was still ineffective. He underwent extensive therapy in the off-season and made it into the lineup in 1991. Mattingly was still an above-average hitter, but the injuries had robbed him of much of his power. He played five more seasons, but never again batted higher than .304 (and that was in the strike-shortened 1994 season) or hit more than 17 home runs.

In 1995 Mattingly finally reached the postseason with the Yankees. He proved he was a big time player by providing dramatic hits during the divisional playoffs against the Seattle Mariners and batting .417 in five games; however, the Yankees lost the series in five games after being up two games to none.