Francona grew up outside of Pittsburgh, Pennsylvania and got his start in baseball at New Brighton, Pennsylvania High School, where he excelled under the coaching of Greg "Faz" Fazio. His father was Tito Francona, who played in the majors from 1956 to 1970, and went to a neighboring high school near Pittsburgh.

Francona was drafted out of the University of Arizona in the first round of the 1980 amateur draft by the Montreal Expos, using the 22nd overall selection. At Arizona he earned the Golden Spikes Award in 1980 as the best player in amateur baseball.

The left-hander wasted no time rising through the minor leagues, first appearing in a Montreal uniform August 19, 1981, a week after the end of that summer's player strike. Francona appeared mainly as an outfielder that first year, and he went 4-for-12 in the National League Division Series against the Philadelphia Phillies, an extra playoff round utilized that year because the season was conducted in two halves as the result of the strike. The Expos won that series, three games to two.

As the seasons went on, Francona shifted to first base, where he ultimately played a hundred games more than he had in the outfield. He also developed a reputation as a contact hitter, with very few home runs, walks, or strikeouts.

The Expos released Francona after the 1985 season, during which his batting average had slipped to .267 after posting a .346 average in limited action in 1984. He went on to sign one-year contracts with the Chicago Cubs, Cincinnati Reds, Cleveland Indians, and Milwaukee Brewers. The Brewers re-signed Francona for 1990, but he only played in three games for the Brewers that year, the last on April 19. In ten seasons and 708 games, he posted a .274 career average, with 16 homers and 143 RBI.

Francona's first managerial job was with the Chicago White Sox organization, heading their Class-A minor league affiliate, the South Bend White Sox. In 1993, he was promoted to the Double-A affiliate Birmingham Barons and in his first year with the club won the Southern League crown, earning him Baseball America's Manager of the Year honors. The following year, the team was swamped by press coverage when NBA star Michael Jordan joined the team in an effort to start a baseball career. Perhaps because of this exposure, Baseball America named him the "top managerial prospect" in the minors in 1994.

Francona's major league managerial career began with the Philadelphia Phillies, where in four seasons (1997 through 2000) the club never rose above third place in the National League East division. His best finish with the Phillies was 77-85 in 1999.

The Red Sox hired Francona to manage their club in 2004, after his predecessor, Grady Little, was not resigned to a contract as a result of the perception that he mismanaged the team in the 2003 American League Championship Series, won by the New York Yankees in seven games.

Francona led the Red Sox to a 98-64 record in 2004, the second-best record in the American League behind the division-rival Yankees. Under Francona's leadership, the club jelled in the second half and was the hottest team in baseball after the All-Star break.

As the American League wild card, the Red Sox dispatched the AL West champion Anaheim Angels, three games to none, in the Division Series. In the 2004 American League Championship Series, the Red Sox fell behind the Yankees, three games to none, including a 19-8 loss in Game 3 at Fenway Park, the home of the Red Sox. However, under Francona's guidance, the club regained its composure and won the last four games of the series, the first time in Major League history that a team rallied from an 0-3 deficit to win a playoff series. Francona's management of his bullpen staff in the four victories was generally regarded as outstanding. The Red Sox then swept the St. Louis Cardinals, four games to none, in the 2004 World Series.

Through the 2005 season, Francona's career regular-season managerial record is 478-494 (.492).