In 2004 he became the sixth manager in history to win pennants with both American and National League teams. With a 2214-1908 record as a manager, he is ranked third all-time for total number of career wins, trailing only Connie Mack (3,731) and John McGraw (2,763). He is one of only two managers to be named Manager of the Year in both of baseball's major leagues.

La Russa (often misspelled LaRussa) was signed by the Kansas City Athletics as a middle infielder prior to the start of the 1962 season. He came up to the A's the next season, making his debut on May 10, 1963. In the following off-season he suffered a shoulder injury while playing softball with friends, and the shoulder continued to bother him during the remainder of his playing career.

Over the next six seasons, La Russa spent most of his time in the minor leagues, making it to the now-Oakland A's roster in 1968 and 1969. He spent the entire 1970 season with the big club, and then late in 1971 the A's traded him to the Atlanta Braves. His final big league playing stop was with the Chicago Cubs, where he appeared as a pinch-runner in one game, on April 6, 1973. He also spent time in the organizations of the Pittsburgh Pirates, Chicago White Sox, and St. Louis Cardinals.

Before becoming a manager, he earned a Juris Doctor (J.D.) degree from Florida State University, but never entered the legal profession. La Russa has been quoted as saying, "I decided I'd rather ride the buses in the minor leagues than practice law for a living." He is the sixth major league manager in baseball history to have earned a law degree, the previous five being Monte Ward (New York Giants, Brooklyn and Providence, late 1800s), Hughie Jennings (Detroit, 1907-20, New York Giants, 1924), Miller Huggins (St. Louis Cardinals and New York Yankees, 1913-29), Muddy Ruel (St. Louis Browns, 1947), and Branch Rickey (St. Louis Browns, 1913-15, St. Louis Cardinals, 1919-25, later the creator of the modern farm system in baseball and still later the executive who broke the color line by signing Jackie Robinson). All of La Russa's attorney-manager predecessors except Ruel are in the Hall of Fameďż˝ Ward as a player, Jennings and Huggins as managers, and Rickey for his accomplishments as an executive.

The White Sox hired La Russa as their manager two-thirds of the way through the 1979 season. He was named American League Manager of the Year in 1983, when his club won the AL West but fell to the Baltimore Orioles in the American League Championship Series. The White Sox fired La Russa after the club got off to a 26-38 start in 1986.

La Russa had a vacation of less than three weeks before his old club, the Athletics, called him to take over as manager. With the A's, he led the club to three consecutive World Series, from 1988 to 1990, sweeping an earthquake-delayed Series from the San Francisco Giants in 1989. In 1988 and 1990, La Russa's Athletics lost the World Series to the Los Angeles Dodgers and the Cincinnati Reds in significant fashion, despite the fact that the A's were heavily favored on both occasions. He earned two additional Manager of the Year awards with the A's, in 1988 and 1992, again winning the Western Division in the latter year.

After the 1995 season, in which the A's finished 67-77, the Haas family, with whom La Russa had a close personal relationship, sold the team after the death of patriarch Walter A. Haas, Jr. La Russa left to take over the helm of the St. Louis Cardinals. The team promptly won the National League's Central Division crown in 1996, a feat his club repeated in 2000, 2001, 2002 (his fourth Manager of the Year award),2004, and 2005. He became the first manager to win the award four times. La Russa's fourth Manager of the Year award was arguably the most emotional; La Russa led the Cardinals to the National League Championship Series (where they would ultimately lose in five games to the San Francisco Giants) in a year in which the Cardinals were traumatized by the deaths of beloved Hall of Fame broadcaster Jack Buck and 33-year-old pitcher Darryl Kile just four days later.

However, it was not until 2004 that the Cardinals finally won the National League pennant under La Russa. The team had the best record in the majors at 105-57, and defeated the Los Angeles Dodgers, 3 games to 1, in the National League Division Series, and the Houston Astros, 4 games to 3, in the NLCS. That put the club in the 2004 World Series against the Boston Red Sox, the Cards' first Series appearance since 1987. However, they were swept by the Red Sox, losing four games to none.

As of 2005, La Russa's regular season managerial record is 2214-1908 (.537), including 894-725 (.552) with the Cardinals. He credits Paul Richards with first inspiring him to believe he could succeed as a major league manager.

It was as a player with the A's that La Russa first met catcher Dave Duncan, who would join his coaching staff in Chicago in 1983. The two have worked together on every La Russa-managed team ever since, and he often credits Duncan as playing a key role in his success.