Fisher made his major league debut in relief on April 14, 1959 against the New York Yankees at Memorial Stadium. He pitched three innings in the 13–3 loss, giving up seven hits, two walks, four runs (two earned), and striking out five. His first strikeout victim was All-Star catcher Elston Howard, the second batter he faced.

In an eleven-season major league career, Fisher posted a 86–139 record with 1,017 strikeouts and a 4.06 ERA in 1,975.2 innings pitched, including 9 shutouts and 62 complete games. He had a batting average of .125 in 594 at bats with one home run, hit against Bobby Locke of the Cleveland Indians on August 7, 1960.

The home starting pitcher in the first game ever at Shea Stadium, Fisher received the honor of throwing the stadium’s first official pitch in 1964. Overwhelmed by the crowd noise and pre-game pomp, Fisher recounts that he asked Mets manager Casey Stengel if he could warm up in the bullpen rather than on the field’s pitcher’s mound, and credits himself with starting that day the big league custom of starting pitchers warming in the bullpen before the game.

Fisher’s busiest seasons were with the early New York Mets. In four seasons (1964–1967) with the perennial losers he won 38 games, lost 73, and had an ERA of 4.58 in 931.2 innings pitched. (The Mets played .355 ball during this time.) Fisher led the National League twice in losses (1965 and 1967) and three times in earned runs allowed (1964, 1965, and 1967). In 1965 he lost 24 games, still tied with Roger Craig for the most since 1935. In 1967, however, Fisher pitched the lowest-hit complete game of his career, a two-hit shutout over the Philadelphia Phillies (June 21 at Connie Mack Stadium).

Pitching for the White Sox in 1968, Fisher had a record of 8–13 with a 2.99 ERA, the lowest of his career. In 1969 he was 4–4 with Cincinnati and was traded to the California Angels in the off-season. He was released by the Angels on April 7, 1970 (Opening Day), and his big league career was over at the age of 31.

Following his retirement from baseball, Fisher settled in Easton, Pennsylvania, where he lives five blocks from former world heavyweight boxing champion Larry Holmes. He once owned Fat Jack’s, an Easton sports bar he sold in 1998. Fisher was inducted into the Academy of Richmond County (his high school) Hall of Fame in October 2017. ARC won seven consecutive state championships from 1951 to 1957. Fisher played on four of those teams. Jack Fisher Way on the school’s campus is named for him.