Nicknamed Fat Freddie (he carried as much as 205 pounds (93 kg) on his 5 feet 11 inches (1.80 m) frame),[1] and known for his mastery of the knuckle curve, Fitzsimmons' 217 wins were the third most by a National League (NL) right-hander in the period from 1920 to 1955, trailing only Burleigh Grimes and Paul Derringer.

He was an agile fielder in spite of his heavy build, holding the major league record for career double plays (79) from 1938 to 1964, and tying another record by leading the league in putouts four times; he ranked eighth in NL history in putouts (237) and ninth in fielding percentage (.977) when his career ended.

After seasons of 14 and 17 wins, he earned a career-high 20 victories in 1928, a year which saw the arrival of teammate Carl Hubbell; until Fitzsimmons' departure in 1937, the two formed a formidable left-right combination at the heart of the Giants' staff.

In 1933, the first full season after Bill Terry took over from John McGraw as manager, he won 16 games with a 2.90 earned run average as the Giants won the NL pennant; in the 1933 World Series against the Washington Senators, he suffered a 4–0 defeat in Game 3, though it was New York's only loss as they captured their first title since 1922.

Fitzsimmons had another 18-win season in 1934, and led the NL in putouts for the fourth time, tying Grover Cleveland Alexander's major league mark.

But he was forced to leave with a 0–0 score after being struck in the kneecap by a line drive hit by Marius Russo, which caromed into Pee Wee Reese's glove to end the inning.

The following day, the tail-ending Philadelphia Phillies tabbed him as their manager, replacing Bucky Harris and ending Fitzsimmons' playing career.

After World War II, Fitzsimmons became a coach with the Boston Braves (1948), Giants (1949–1955), Chicago Cubs (1957–1959; 1966), and Kansas City Athletics (1960).