The Baltimore Orioles selected Don Baylor in the second round of the 1967 MLB draft. He received a $7,500 signing bonus from the Orioles. In 1970, he led the league with 34 doubles, 15 triples, 127 runs, and 140 games-played while playing for Rochester. The following year, he again led the league in doubles with 31 for Rochester. Baylor played for the Orioles from 1970 to 1975. Before the 1976 season, the Orioles traded him with Paul Mitchelland Mike Torrez to the Oakland Athletics for Reggie Jackson, Ken Holtzman and Bill VanBommell. In 1977, Baylor signed with the California Angels as a free agent. He led the American League (AL) with 139 run batted in (RBIs) and 120 runs in 1979, and was an AL All-Star. He won the AL’s MVP award and led the Angels to their first ever AL Western Division title. Baylor signed with the New York Yankees in 1983. He was traded to the Boston Red Sox for Mike Easler in 1986. In 1987, he was traded to the Minnesota Twins for a player to be named later (Enrique Rios). He signed with the Athletics for 1988, his final season as a player. Don Baylor reached the World Series three times in his career, in consecutive years with three different teams (one of two players in history to accomplish this feat; Eric Hinske is the other)—the Red Sox in 1986, the Twins in 1987, and the A’s in 1988—and was on the winning side in 1987. Baylor was a power hitter known for crowding the plate. He set the Red Sox’ team record for most hit by pitches in a season (35 in 1986); in his career, he was hit by pitches 267 times, fourth most all time. Baylor retired with 285 stolen bases, 2,135 hits, and 338 home runs.

After retiring as a player, Don Baylor served as a hitting coach for the Milwaukee Brewers and St. Louis Cardinals until he was named the manager of the expansion Colorado Rockies. He led the team for six years from 1993–98. The Rockies posted their first winning record (77–67) in 1995 and made the postseason as the wildcard team, and as a result, Baylor won the National League Manager of the Year Award. After the 1998 season, Baylor was fired. He finished his Rockies managerial career with a regular season record of 440–469 and a post–season record of 1–3. He became the hitting coach for the Atlanta Braves in 1999 and was hired to manage the Chicago Cubs in 2000 and managed through 2002. He had a record of 187–220 with the Cubs. From 2003 to 2004, he served as the bench coach for the New York Mets. He spent the 2005 season with the Seattle Mariners as hitting coach under manager Mike Hargrove, and was as a fill-in analyst for MASN in 2007 on Nationals broadcasts. Baylor served as hitting coach for the Colorado Rockies during the 2009 and 2010 seasons. Baylor was replaced by Carney Lansford after the Rockies hit a franchise-low .226 on the road during the 2010 season. Don Baylor was offered a special assistant position to remain with Colorado but turned it down.

Don Baylor agreed on a two-year contract to become hitting coach for the Arizona Diamondbacks for the 2011 and 2012 seasons. He was hired by the Los Angeles Angels of Anaheim as their hitting coach for the 2014 season. On March 31, 2014, Baylor suffered a fracture to his right femur while catching the ceremonial first pitch of the 2014 season, thrown by Vladimir Guerrero. On April 1, 2014, he had surgery to have a plate and screws inserted into his leg. On October 13, 2015, the Angels announced that Baylor would not return as the team hitting coach in 2016. Don Baylor was diagnosed with multiple myeloma in 2003. He died on August 7, 2017, at the age of 68.