As a manager, he was very successful; his .597 winning percentage is second all-time to Joe McCarthy's .615. Southworth's Major League managerial won-loss record was 1,044–704 with four first-place finishes, and he won two World Series titles (1942, 1944) as manager of the St. Louis Cardinals. Southworth also won one World Series as a player (1926, also with the Cards). Southworth was the first to win the World Series as a player and again as a manager. However, his career as a manager was paved with obstacles.
Southworth, a player-manager who was only one year removed from being a teammate of his charges, attempted to impose discipline on the Cards, banning them from driving their own automobiles. But the Redbirds did not respond to his hard line and won only 43 of their first 88 games. Southworth was sent back to Rochester and McKechnie was rehired. Although Southworth immediately resumed his successful minor league managerial career, the firing and personal tragedy — the death of his first wife, Lida Southworth, at age 42 — began a downward spiral. Beset by struggles with alcoholism, he even left baseball for two seasons. Finally, after a recovery, he rejoined the Cardinals' minor league system in 1935 and by 1939 he was again enjoying success as Rochester's manager.
In June 1940, he received a second chance with the struggling Cardinals when owner Sam Breadon fired manager Ray Blades and promoted Southworth from Rochester. This time, the Cards flourished under him. With talented players such as Enos Slaughter, Marty Marion, Stan Musial, Walker Cooper, Mort Cooper, Whitey Kurowski and Johnny Beazley being harvested each spring from the club's farm system, the Cardinals entered a Golden Age in their history. Upon Southworth's appointment, they won 69 of 109 games and jumped from seventh to third place in 1940. The following season they won 97 games and finished second.
But another personal tragedy awaited Southworth. On February 15, 1945, his son, MajorWilliam Brooks Southworth, USAAF — also a professional baseball player — died in a plane crash in Flushing Bay, New York, during military flight training. Still, the Cards' skipper began managing at the beginning of the 1945 season; the Redbirds won 95 games but finished second, three games behind the Chicago Cubs.
The following season saw Boston struggle on the field and in chaos off the diamond. Southworth was rumored to be drinking heavily and near nervous collapse, and some players resented his rules and regulations and the amount of credit he had received for the 1948 pennant. With Boston at 55–54 in August, Southworth turned the Braves over to coachJohnny Cooney for the remainder of 1949. After some of the rebellious players (including starting shortstopAlvin Dark and second basemanEddie Stanky) had been traded, Southworth returned to his post in 1950 and led the Braves back into the first division, but an aging team and declining attendance bode poorly for both Southworth's career and the Braves' future in New England. In 1951, Southworth's club was only 28–31 on June 19 when he was fired and replaced by his former standout right fielder, Tommy Holmes. While he remained with the Braves as a scout, Southworth never managed again in the Major Leagues and the Braves abandoned Boston for Milwaukee in March 1953.
Billy Southworth died of emphysema in 1969 in Columbus, Ohio, at the age of 76, and was buried in Green Lawn Cemetery. On the occasion of Southworth's election to the Hall of Fame, one of his former players on the 1948 Braves, Clint Conatser, paid tribute to his old manager. "He just had a gut feeling about the right thing to do in a situation," Conatser recalled. "The moves he would make would work for him — all the time, not occasionally. Leo Durocher was the same way. It's like some guys can pick horses out of nowhere. Southworth was a genius like that on the diamond."