Known for his versatility, Sisti played every position except pitcher and catcher during his big league career. He made his major league debut with the Boston Bees on July 21, 1939 and remained with the club (later known as the Braves) until World War II. He served in the United States Coast Guard from 1943 to 1945. After returning from the war, the Braves had no place for him in their lineup, and he spent most of 1946 with the Indianapolis Indians of the American Association. He hit .343 for the club and was named Minor League Player of the Year by The Sporting News.
The following year he returned to the Braves. In 1948, he played a key role in the club's run to the World Series, filling in for injured second base Eddie Stanky for part of the season. He remained with the team when they became the Milwaukee Braves in 1953 and retired in 1954 to join their coaching staff.
The last page of The Great American Baseball Card Flipping, Trading and Bubble Gum Book (by Brendan C. Boyd & Fred C. Harris, Little Brown & Co, 1973) had a card of Sisti in his Braves uniform, catching a ball, with the authors' caption, "Goodnight, Sibby Sisti, wherever you are."
Sisti answered that implied question by appearing in a small role in the 1984 film The Natural, portraying the Pittsburgh manager. He was also a consultant on the film, making sure it captured the feel of 1930s baseball.
He was a first cousin of Danny Carnevale, a minor league manager, and made the majors in 1970 with the Kansas City Royals (first base coach).