Darnell Coles embarked on his professional baseball journey when he was drafted by the Seattle Mariners as the sixth overall pick in the first round of the 1980 Major League Baseball Draft. His debut in the major leagues came on September 3, 1983, with the Mariners. Coles, primarily a third baseman, also played in the outfield and occasionally at shortstop, showcasing his adaptability on the field.

During his time with the Mariners, Coles showed potential but struggled to find consistency at the plate. In 1986, he was traded to the Detroit Tigers, where he experienced one of his best seasons. That year, Coles hit 20 home runs and drove in 86 runs, achieving a .273 batting average. His performance helped solidify his role as a valuable player in the Tigers' lineup.

Coles' career saw him moving between several teams, including the Pittsburgh Pirates, San Francisco Giants, Cincinnati Reds, Toronto Blue Jays, St. Louis Cardinals, and Colorado Rockies. His ability to play multiple positions made him a useful asset for these teams, although he often served as a utility player rather than a regular starter.

In 1993, Coles returned to the Seattle Mariners, the team that had originally drafted him. This stint was short-lived, and he continued to move between teams, finishing his major league career with the St. Louis Cardinals in 1997. Over his career, Coles played in 957 games, achieving a batting average of .245, with 75 home runs and 368 RBIs.