After a shoulder injury during the 1964–65 off-season, he returned to college and received a degree from the University of South Florida before playing much of the remainder of his career in the minor leagues until retiring in 1977.

Three months later, he accepted a position helping fellow former manager Joe Torre, the executive vice president for MLB operations.

[2][6] La Russa made his major league debut with the Kansas City A's on May 10, 1963, after having played 76 games with A's affiliates Binghamton Triplets and Daytona Beach Islanders in 1962.

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, scoring the walk-off winning run.

La Russa spent a half-season at Knoxville before being promoted to the White Sox coaching staff when owner Bill Veeck changed managers from Bob Lemon to Larry Doby.

Doby was fired at the end of the season; Don Kessinger, former star shortstop of the crosstown Cubs, was named the White Sox' player-manager for 1979, and La Russa was named manager of the Triple-A Iowa Oaks of the American Association, choosing to manage in the minors after the White Sox had offered him his same major league coaching role.

In their third consecutive appearance, the favored A's faced manager Lou Piniella, LaRussa's childhood teammate and friend, and his Cincinnati Reds in the 1990 World Series.

On September 10, 2003, he won his 2,000th career game as a manager against the Colorado Rockies, becoming the seventh to reach the mark in Major League Baseball.

[30] La Russa led the Cardinals to the 2011 World Series, after defeating the Philadelphia Phillies in the NLDS (3–2), and then the Milwaukee Brewers in the NLCS (4–2).

[18] La Russa also became the first manager in Major League Baseball history to retire in the same season after winning a World Series title.

[32] Even though he had retired, La Russa managed the National League All Stars in the 2012 MLB All-Star Game for the final time as a member of the Cardinals.

After serving in various executive roles for MLB and for several teams, La Russa was announced as the manager of the White Sox on October 29, 2020, replacing Rick Renteria.

The decision immediately backfired as the next batter, Max Muncy, hit a home run just a few pitches later that made the score 9–5 in an eventual win for the Dodgers.

[41] On August 30, La Russa, under the advice of a cardiologist he had seen about his heart, elected to not manage the impending game versus Kansas City.

On that same day, the White Sox announced that La Russa was out indefinitely, with bench coach Miguel Cairo taking over as interim manager.

Shortly after his retirement from the playing field, La Russa took a position with MLB assisting former managerial rival Joe Torre in matters of on-field discipline.

At that time, it held the highest annual average value in MLB, exceeding $34.4 million per year, and was also the largest contract by total value in team history.

[52] La Russa is second in major league history in victories as a manager (2,884), trailing only Connie Mack (3,731) and surpassing John McGraw (2,763) on June 6, 2021.

[56][57] After the retirement of Atlanta Braves manager Bobby Cox in 2010, La Russa was the longest tenured manager in Major League Baseball, and with the resignation of longtime NBA head coach Jerry Sloan from the Utah Jazz on February 10, 2011, La Russa had been the longest tenured bench boss among all the Big Four sports leagues, until his retirement following his 2011 World Series victory with the Cardinals.

On November 4, 2013, La Russa's inclusion on the Expansion Era ballot was announced with fellow former Cardinals Ted Simmons, Joe Torre and Dan Quisenberry.

[citation needed] In 2007, at a concert in San Francisco on La Russa's birthday, Hornsby played a comedic song he named "Hooray For Tony".

[66] La Russa was also inducted into the Hispanic Heritage Baseball Museum Hall of Fame on April 11, 2008, in a pregame ceremony at AT&T Park.

[citation needed] In 1980, La Russa appeared as a contestant on the game show To Tell The Truth, and helped fool the celebrity panel.

[75] On June 4, 2009, the St. Louis Post-Dispatch reported that La Russa had sued the online social network platform Twitter the previous month for a fake page established under his name on the site.

[80] Calling his arrest on the DUI charge an "embarrassment", La Russa apologized to "anyone who is close to me, members of the Cardinals organization, our fans."

In a statement released by his attorney, La Russa said, "I accept full responsibility for my conduct, and assure everyone that I have learned a very valuable lesson and that this will never occur again".

In February 2020, La Russa was charged with DUI again, this time in Phoenix; the case was filed on October 28, 2020, a day before he was rehired by the White Sox.

In 2012, La Russa released his New York Times bestselling memoir, One Last Strike, which recounts his legendary last season as manager of the St. Louis Cardinals and their remarkable journey to becoming the 2011 World Series Champions from ten and a half games back.

As David Leonhardt of The New York Times wrote of the "stats vs. hunches" debate in an August 29, 2005 piece, "what makes this fight truly comparable to those that periodically roil the world of art history or foreign policy is that the differences between the sides are not as great as the sniping between them suggests.

The games won numerous awards and featured "new" statistics selected with La Russa (and provided by prominent sabermetrics authors John Thorn and Pete Palmer) as tools for players as they managed their teams.