In 1919, Frisch left Fordham  to sign with the New York Giants of the National League, moving directly to the majors without playing in the minor leagues. He made an immediate impact, finishing third in the NL in stolen bases and seventh in RBI in 1920, his first full season. Manager John McGraw was so impressed by Frisch that he soon named him team captain, giving him advice in baserunning and hitting. The Giants played Frisch at both third base and second base early in his career, but by 1923 he was installed as the team's full-time second baseman.
Frisch batted over .300 in his last six seasons with New York. He was also an expert fielder and a skilled baserunner. In 1921, he led the National League with 48 steals, in 1923 in hits, and in 1924 in runs. With Frisch adding his fiery competitiveness to the team, the Giants won the World Series in 1921 and 1922, winning the NL pennant the following two seasons as well.
Frisch is tied with Pablo Sandoval for the franchise post-season multi-hit games record of 15.
After the 1926 season, Frisch was traded – with pitcher Jimmy Ring – to the St. Louis Cardinals in exchange for star Rogers Hornsby. After an August 1926 loss in which Frisch had missed a sign, costing the Giants a run, McGraw had loudly berated Frisch in front of the team; Frisch responded by leaving the team, and his previously close relationship with McGraw virtually ended.
Playing second base for the Cardinals, Frisch appeared in four more World Series (1928, 1930–31, 1934), bringing his career total to eight. He was the driving force of the "Gashouse Gang", the nickname for the Cardinals clubs of the early 1930s, which were built around him to reflect his no-holds-barred approach. The Cardinals had won only one pennant before Frisch joined the team; the Giants would win the pennant only once in Frisch's nine seasons as the Cards' regular second baseman.
Frisch became player-manager of the Cardinals in 1933, and was named to the NL's first three All-Star teams from 1933-35. In 1934, he managed the Cardinals to another seven-game World Series victory – this time over the Detroit Tigers.
Frisch finished his playing career in 1937. His career statistics totaled a .316 batting average, still the highest ever for a switch hitter, with 2880 hits, 1532 runs, 105 home runs and 1244 RBI. He also stole 419 bases in his nineteen playing seasons. His hit total stood as the record for switch-hitters until Pete Rose surpassed it in 1977. Frisch also hit .300 for his career from each side of the plate; the only other switch-hitter with more than 5,000 at-bats with this distinction is Chipper Jones.
Frankie Frisch was elected to the Baseball Hall of Fame in 1947. After no players had been selected by the writers in the previous two years (the only elections since 1942), the rules were revised to limit eligibility to those players who had retired after 1921; Frisch was among the first four players to benefit from the more reasonable field of candidates.
After his retirement as an active player, Frisch continued to manage the Cardinals, but was never able to capture another pennant. Frisch also had managerial stints with the Pittsburgh Pirates (1940–46) and the Chicago Cubs (1949–51), but without the success he had in St. Louis. Frisch's career ledger as a manager shows a 1,138–1,078 (.514) mark, including the pennant in 1934. He also spent the first two months of the 1949 season as a New York Giants' coach, working under his old double-play partner, Leo Durocher, before leaving June 14 to replace Charlie Grimm as manager of the Cubs.
Frisch also worked for several years as a baseball color commentator on radio and television. In 1939, he called games for the Boston Bees and the Boston Red Sox on the Colonial Network, a regional radio network serving five New England states. He also called Giants radio in 1947-48, then worked as a post-game host for the team's telecasts in the 1950s. His broadcasting trademark was worrying about pitchers walking batters: "Oh, those bases on balls!" After a heart attack in September 1956 forced Frisch to curtail his activities, Phil Rizzuto (recently released by Yankees as a player) filled in for him on Giants post-game shows for the rest of the season. From 1959-61, Frisch teamed with Jack Whitaker to form the backup crew for Saturday Game of the Week coverage on CBS.
A number of years after Frisch left the playing field as a manager, he became a member of the Hall of Fame's Committee on Baseball Veterans, which is responsible for electing players to the Hall of Fame who had not been elected during their initial period of eligibility by the Baseball Writers; he later became chairman of the committee. In the years just prior to his death, a number of Frisch's Giants and Cardinals teammates were elected to the Hall; some notable writers, chiefly among them Bill James, have criticized these selections – including Jesse Haines, Dave Bancroft, Chick Hafey, Rube Marquard, Ross Youngs and George Kelly – which include some of the most widely questioned honorees in the Hall's history. Critics have complained that many of these selectees had accomplishments which were less outstanding than those of other players who were bypassed, and were only selected because of Frisch's influence.
During his lifetime, Frisch used 1898 as his year of birth, although other records (Social Security death index, Census records, World War I Draft registration, and passport application) indicate an 1897 birth.
Years later, Nash added a footnote to this stanza: "p.s. Thanks to Durocher, now everything's kosher."
For many years, he lived at 184 Fenimore Road in the Bonnie Crest neighborhood of New Rochelle, New York. He had two hounds named Flash and Patches who kept him company. Frisch eventually moved to Charlestown, Rhode Island, devoting himself mainly to his interests in gardening and classical music.