Known as "Ersk", or more accurately "Oisk", owing to the Brooklynese diction of the borough, Erskine signed with the Brooklyn Dodgers in 1946, and after two minor league seasons he made the team in July as part of a powerful squad that included Roy Campanella, Carl Furillo, Gil Hodges, Pee Wee Reese, Jackie Robinson and Duke Snider. Along with Snider and Reese, he lived in the Brooklyn neighborhood of Bay Ridge, and was frequently to be found around the baseball diamonds on Shore Road, offering encouragement to youngsters.

1948-1956

He broke into the majors a year before Don Newcombe , and from 1948-50 was used primarily as a reliever, going 21-10. In 1951, he mixed 19 starts with 27 relief appearances, and went 16-12. For the following five seasons, he was right at the heart of Brooklyn's rotation, especially with his work in 1952-53, which was crucial for the NL pennant winners due to Newcombe serving in the army from 1952 until mid-1954. Erskine was 14-6 in 1952 with a career-best 2.70 earned run average, then had his 20-win season in 1953, leading the league with a .769 winning percentage along with 187 strikeouts and 16 complete games, all career highs. This was followed by 18-15 in 1954, posting career highs in starts (37) and innings (260-1/3), then by 11-8 in 1955 and 13-11 in 1956.

Erskine, author of two no-hitters, (against the Chicago Cubs on June 19, 1952 and the New York Giants on May 12, 1956), was a member of the beloved Dodgers team which won the 1955 World Series for the franchise's first Series title. He appeared in eleven World Series games (1949-52-53-55-56), and made the NL All-Star team in . His 14 strikeouts as the winner of Game 3 of the 1953 Fall Classic – including striking out the side in the ninth inning – broke the Series record of 13 held by Howard Ehmke (1929, Game 1), and stood for 10 years until Sandy Koufax struck out 15 New York Yankees in the first game of the 1963 World Series; but he was ineffective in Games 1 and 6, although he was not charged with the losses. From 1951 through 1956, Erskine won 92 games while losing only 58, which helped the Dodgers to four pennants during the "Boys of Summer" era.

1957-1959

Then in 1957, like so many of his Dodgers teammates, Erskine began his final decline. He moved to Los Angeles with the team the following year, but lasted only a season and a half. The long decline of his career had actually been set in motion during his rookie year when he injured his shoulder in his first major league start, yet not only finished the game but started twice more in extreme pain. So serious was the injury, in which he pulled a muscle away from his shoulder bone, that he was unable to throw between starts; by 1957, at only 31, he was on his way out, and he made his final appearance on July 14, 1959. In a twelve-season career, he posted a 122-78 (.610) record with 981 strikeouts and a 4.00 ERA in 1718.2 innings pitched.

Following his retirement as a player, Erskine returned to his native Indiana. His leadership capabilities which have made him a successful businessman were also apparent during his playing days, as he served as a team Player Representative for eight years. He coached at Anderson College for 12 seasons, including four championships. He has gone on to be a leader in the community, participating in numerous organizations and businesses. Erskine rose to the presidency of the Star Bank of Anderson, Indiana before easing back to the role of vice chairman of the board. He is devoted to his son Jimmy, who has Down syndrome, and granddaughters Abbey and Dannae, and lives at home and holds a job nearby at the Hopewell Center for people with developmental difficulties.

To commemorate Erskine's accomplishments both as a Dodger and as a citizen, a bronze statue was erected in front of the Carl D. Erskine Rehabilitation and Sports Medicine Center. Also, Erskine donated part of his land to the Anderson Community School System to build a new school, which was named Erskine Elementary.

Currently, Erskine serves as a member of the advisory board of the Baseball Assistance Team, a 501(c)(3) non-profit organization dedicated to helping former Major League, Minor League, and Negro League players through financial and medical difficulties.

Erskine is also a very active member of the First Baptist Church of Anderson, IN.

In 2002, Erskine Street in Brooklyn was created and named after him.