Majkowski attended the University of Virginia, and became the starting quarterback for the Virginia Cavaliers partway into the 1983 season, his first year there. Majkowski led the Cavaliers to the school's first ever bowl appearance and bowl win, in the 1984 Peach Bowl. During his college career, Majkowski's jersey number was "1".
Majkowski was drafted by the Green Bay Packers in the 10th round in 1987. He was originally issued jersey #5, but switched to #7 the following season in anticipation that #5 would be retired for Paul Hornung. The jersey was never officially retired, but Majkowski is still the last Packer to have worn #5. As a rookie, Majkowski split time with Randy Wright, with whom he also shared quarterback duties during the 1988 season. During the 1987 season Majkowski's salary was $65,000; he also received a $10,000 roster bonus.
Nicknamed The Majik Man, Majkowski broke out during the 1989 Green Bay Packers season. He was given the starting job and Randy Wright was released. Majkowski had one of the finest seasons in Packers history. He completed 353 passes in 599 attempts. His 4,318 passing yards led the NFL. He also threw for 27 touchdowns. Notably, the Packers won their first game against the hated rival Chicago Bears since 1984. The key was a touchdown play, first nullified by an illegal forward pass by Majkowski, then upheld by instant replay as a legal pass. The season ended with 10 wins and 6 losses; Majkowski capped the season with his being selected to the Pro Bowl.
Majkowski's success was cut short when, in the 10th game of the Packers' 1990 season, Majkowski was injured when he was upended and tackled on his shoulder by Freddie Joe Nunn. Nunn drew a personal foul on the play. At first thought to be a bruise, Majkowski's injury turned out to be more serious, a torn rotator cuff. The Packers finished the season using backups Anthony Dilweg and Blair Kiel. During the course of the 1991 season, Majkowski was benched and replaced by Mike Tomczak as starter, but resumed starting duties at the beginning of the 1992 season. On a play on September 20, 1992 against the Cincinnati Bengals, Majkowski tore a ligament in his ankle. He was replaced after the play by Brett Favre, who completed the game. Favre went on to start in every consecutive Packers game through the 2007 season.
Don Majkowski finished his football career for the 1995 and 1996 Detroit Lions as backup quarterback to starter Scott Mitchell. In his final season Majkowski faced Brett Favre and the Green Bay Packers on November 3, 1996 completing 15 of 32 passes for 153 yards, 1 TD and no interceptions in a 28-10 Lions loss. He was also sacked 5 times. Majkowski's final start was played in Detroit in a win against the Seattle Seahawks. He completed 18 of 23 passes (78% completion percentage) for 157 yards, 1 TD and an interception for a passer rating of 91.5. The Lions won the game 17-16 and improved their record to 5 wins and 6 losses. However, this was the last win for the Lions as they finished the 1996 season with a 5-11 won-loss record as Scott Mitchell started all five games.
Majkowski is a real estate investor and contractor, and currently lives in Atlanta, Georgia, with his wife (Kelly) and their two children (Dani and Bo). He has done some NFL analyst work in Wisconsin, having done pregame and postgame show with Fox 6 in Milwaukee, as well as various radio and TV programs in Northern Wisconsin. Currently is the Offense Coordinator for his son's 7th Grade Georgia Middle School Athletic Association 6th grade State Champion Johns Creek Gladiators.