Duffy was born in Cranston, Rhode Island to Irish immigrant Michael Duffy and wife Margaret Duffy. A right-handed batter and thrower, Duffy was listed as 5 feet 7 inches (1.70 m) tall and 168 pounds (76 kg). He was a textile mill worker who had taken up baseball as a semipro for weekend diversion. He played a couple years of minor league ball in the New England League before jumping to the majors, starting up in the league’s initial season of 1886, and playing on clubs in Hartford, Springfield and Salem, as well as the Lowell, Massachusetts team in 1887.

Duffy entered the National League with Cap Anson’s Chicago White Stockings in 1888 after receiving an offer of $2,000 from the club. Anson initially was unimpressed with the 5 ft 7 in (1.70 m), 150 pound Duffy, telling him, “We already have a batboy.” He shortly thereafter earned the reputation of an outstanding outfielder and powerful hitter. Duffy ended up replacing Billy Sunday as the team’s regular right fielder. He switched leagues, joining the American Association’s Boston Reds in 1891; he then returned to the NL with the Boston Beaneaters in 1892, where he enjoyed his best seasons.

From 1891 through 1900, Duffy knocked in 100 runs or more eight times. In 1894 Duffy had one of the greatest seasons in baseball history, leading the league with 18 home runs, with 145 RBI and a .440 batting average (see Major League Baseball Triple Crown). Duffy’s .440 average is the major league single-season batting average record. At one point during the season, Duffy had a 26-game hitting streak. He was player-manager for the Milwaukee Brewers in 1901. During the 1902 and 1903 seasons, Duffy was player-manager for the Western League’s Milwaukee franchise.

Duffy was a player-manager for the Phillies from 1904 to 1906. He finished his career in 1906 with 106 home runs which was, at the time, one of the highest career totals.

Duffy agreed to manage the Chicago White Sox in 1910. He stayed with the team in 1911. He moved to the Milwaukee Brewers of the American Association in 1912, but he was fired after a season in which the team struggled. He turned down an offer to manage the 1913 St. Paul Saints, saying that he was hoping to work in the east. He coached the Harvard varsity and freshman baseball squads from 1917 through 1919. He also managed the 1920 Toronto Maple Leafs of the International League to a .701 winning percentage—the best in the team’s 83-year history, but only good enough for second place in the league.

In 1921, Duffy was hired as full-time manager of the Red Sox, guiding them for two seasons. Duffy then became a scout for the Red Sox in 1924.

Duffy remained on the Red Sox’ scouting staff nearly to the end of his life, retiring in 1953. He died in Boston on October 19, 1954. He had been suffering from heart problems. Duffy’s wife Nora died the previous year; they did not have children.

In 2019, Duffy was inducted into the Atlanta Braves Hall of Fame, along with Terry Pendleton.