Born in Harvard, Nebraska, Southworth decided to play baseball despite his father's wishes. He batted .300 three times in his career, not counting shortened seasons.

In a 13-season career, he batted .297 with 52 home runs with 561 RBIs. He stole 138 bases in his career. He had 1296 hits in 4359 at bats.

As a manager, he was very successful, almost accumulating a .600 winning percentage (.597). He was 1770-1044 all-time with four first-place finishes, and two World Series titles (1942, 1944). Southworth also won one World Series as a player (1926).

Southworth began his managing career in 1928 with the Rochester Red Wings of the AA International League, the top club in the Cardinals' leading-edge farm system. After winning the IL pennant, he was promoted to St. Louis as manager for 1929, replacing Bill McKechnie, who had won a National League pennant in 1928 but lost the 1928 World Series in four straight games to the New York Yankees.

Southworth, only one year removed from his playing days, 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 45 games. Southworth was sent back to Rochester and McKechnie was rehired. Although Southworth immediately resumed his successful minor league managerial career, the firing 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. This time, the Cards flourished under Southworth. 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. Then, from 1942-44, the Cardinals won 106, 105 and 105 games, three pennants and two World Series titles. Southworth had presided over one of the most dominant three-year stretches in National League history. But in 1945, his son, Major William Brooks Southworth, died in a plane crash during military flight training. The Cards' manager rushed to the scene of the crash and was overcome with sadness, but began managing at the beginning of the season despite the tragedy. The Cardinals finished second that season, three games behind the Chicago Cubs.

Southworth then moved to the Boston Braves in 1946, signing a then-lucrative managing contract for a reported $50,000 per season, and immediately led the Braves into the first division. In 1948, spearheaded by the National League's best one-two pitching combination, lefthander Warren Spahn and righty Johnny Sain, the Braves won their second NL pennant of the 20th century but were defeated in six games by the Cleveland Indians in the 1948 World Series.

The following season saw Boston struggle on the field and in chaos off the diamond, with numerous players rebelling against Southworth's rules and regulations. The manager was rumored to be drinking heavily and near nervous collapse. With Boston at 55-54 in August, Southworth turned the Braves over to coach Johnny Cooney for the remainder of 1949. Southworth returned to his post in 1950 - the rebellious players had been traded - 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. He never managed again in the major leagues and the Braves abandoned Boston for Milwaukee in March 1953.

Billy Southworth died of emphysema at age 76 in Columbus, Ohio.