In 1940 he signed with the Braves organization. His major league career began in 1942 with the Braves and he spent all but one year with that franchise, first in Boston and then in Milwaukee. He finished his career in 1965 with the New York Mets and the San Francisco Giants. Spahn won more games than any other lefty (363) and is the fifth-winningest pitcher ever, trailing only Cy Young (511), Walter Johnson (417), Grover Cleveland Alexander (373), and Christy Mathewson (373) on the all-time list. (Some rank Spahn sixth after 19th-century pitcher Pud Galvin, who won 364 games. But four of Galvin's wins came in 1875 in the National Association. Since there is not consensus about whether the National Association should be considered a "major league", Spahn and Galvin's relative rankings have sparked controversy.)
Spahn also threw two no-hitters, won 3 ERA titles, appeared in 14 All-Star games, and holds the National League record for career home runs by a pitcher with 35. Spahn led the National League in wins eight times, including five seasons in a row (1949, 1950, 1953, 1957-1961) and complete games nine seasons, seven consecutively (1949, 1951, 1957-63); these numbers are major league records.
He pitched in the World Series for the Braves in 1948, 1957, and 1958. During the 1948 season, he combined with teammate Johnny Sain to anchor a pitching rotation that was generally considered to be exceptionally weak otherwise, leading to a popular saying which entered baseball lore as "Spahn and Sain and pray for rain." Spahn served in the United States Army in World War II and was wounded in Europe. He was awarded Purple Hearts and the Bronze Star for bravery. He saw action in the Battle of the Bulge and at the Ludendorff Bridge as a combat engineer, and was awarded a battlefield commission.
Spahn died at age 82, apparently of natural causes, at his home in Broken Arrow, Oklahoma. He is interred in the Elmwood Cemetery in Hartshorne. He was elected to the Baseball Hall of Fame in 1973, his first year of eligibility.