Colvin was called up to the majors for the first time on September 21, 2009. He started the game and went 1 for 3 with a single and a sacrifice fly.
After a strong spring in 2010, Colvin made the Cubs Opening Day roster. On April 8, 2010, against the Atlanta Braves, Colvin hit his first major league home run. Three nights later Colvin hit his first triple of his major league career against the Washington Nationals.
On September 19, 2010, in a game against the Florida Marlins, Colvin was hit in the chest with a shard from a broken bat when scoring on a double by Welington Castillo. The piece of bat punctured Colvin's lung. Colvin was brought to the hospital and remained in stable condition. He missed the remainder of the 2010 season due to the incident.