Francona originally signed with the St. Louis Browns in 1952. He spent two seasons in the Browns/Baltimore Orioles’ farm system (the franchise was relocated to Baltimore and renamed on September 29, 1953) before departing to serve in the U.S. Army for two years. Upon his return, he was invited to Spring training 1956 as a non-roster invitee, and made the club. He batted .258 with nine home runs and 57 runs batted in to finish tied with the Cleveland Indians’ Rocky Colavito for second place in American League Rookie of the Year balloting behind Chicago White Sox shortstop Luis Aparicio.

With Al Pilarcik’s acquisition during the off season, Francona lost his starting job in right field, and was demoted to the Pacific Coast League’s Vancouver Mounties early in the 1957 season. He returned with a vengeance, hitting two home runs in a game for the first time in his career on May 19 against the Kansas City Athletics, raising his season average to an even .300 in the process. He slipped into more of a reserve role from there. Used as a fourth outfielder and left-handed bat off the bench, Francona batted just .185 as a pinch hitter for the season. After which, he, Ray Moore and Billy Goodman were dealt to the Chicago White Sox for Larry Doby, Jack Harshman and Jim Marshall (Chicago later sent pitcher Russ Heman to Baltimore as part of this deal when it was discovered by the Orioles that Harshman was suffering from a slipped disc).

After a hot Spring, Francona won the White Sox starting right field job. His stay in Chicago was short, as he was dealt to the Detroit Tigers on the June 15 trade deadline. With Hall of Famer Al Kaline in right, Francona logged just 84 plate appearances over the remainder of the season. Dissatisfied with his lack of playing time, Francona demanded a trade. On March 21, 1959, he was traded to the Cleveland Indians for Larry Doby, the second trade involving the two.

On March 26, 1961, Francona hit a home run during a spring training exhibition game against the Boston Red Sox at Hi Corbett Field. When John C. Cota, a city parks employee, went to retrieve the ball, he discovered the body of Fred Victor Burden, who was wanted by Tucson, Arizona police in connection with the shooting death of former prize fighter James Cocio.

Despite having emerged as one of the better fielding left fielders in the league, Francona was shifted to first base during Spring training in 1962 and finished the season leading the American League in Double Plays turned as a first baseman. He drew the ire of Boston sports fans at Fenway Park on June 11. With the game still scoreless, the Indians loaded the bases with two outs in the third inning. From first base, Francona yelled, “Hold it, Earl!” to Red Sox pitcher Earl Wilson. Francona’s distraction caused Wilson to half stumble off the mound and balk. Despite this being against baseball rules, Francona admitted after the game that he had indeed yelled to Wilson.

Francona slumped a little under new manager Mel McGaha in 1962. When Birdie Tebbetts grabbed the reins in 1963, Francona was moved back into left, but his numbers dipped even further. His .228 batting average was a career low, and his ten home runs and 41 RBIs were his fewest over a full season. He was, however, part of baseball history on July 31, when he hit the third in a series of four consecutive home runs in a single inning against pitcher Paul Foytack of the Los Angeles Angels. This was the second time in baseball history that a team hit four consecutive home runs in a single inning. It has happened three times since, including once by the Red Sox while his son, Terry Francona, was managing.

His 1000th hit came off Los Angeles Angels All-Star Ken McBride on April 23, 1964.

The World Series champions were already set in their corner outfield positions and at first base; Francona was acquired strictly to strengthen their bench. He batted .259 in 1965, including .265 as a pinch hitter. He remained a pinch hitter with the Cards through 1966. During Spring training 1967, his contract was sold to the Philadelphia Phillies.

Francona batted .205 with three RBIs filling in for an injured Bill White at first base for the Phillies. Upon his healthy return, Francona was sold to the Atlanta Braves. He enjoyed something of a resurgence in Atlanta, batting .248 with six home runs and 25 RBIs over the remainder of the 1967 season. In 1968, he logged 398 plate appearances, his most since 1963, and batted .296 with 47 RBIs, his most since 1962.

Francona was batting .339 with fourteen RBIs in semi-regular action in 1969 before a dislocated thumb halted his season. He returned healthy toward the end of June, but batted just .219 with one home run and eight RBIs in his return before his contract was sold to the Oakland A’s on August 22. He returned to his hitting ways, batting .341 with three home runs and twenty RBIs over the rest of the season. He split the 1970 season between the A’s and Milwaukee Brewers before retiring.

Francona was the director of parks and recreation in New Brighton, Pennsylvania until retiring in 1997. He remained in New Brighton until his death at his home on February 13, 2018.