La Russa and the White Sox agreed to terms on a multi-year contract, according to Scott Merkin of MLB.com.
The 76-year-old Hall of Famer last managed in the majors in 2011, when he led the St. Louis Cardinals to a World Series title. He's won three career championships and sits third on the all-time list with 2,728 managerial victories.
La Russa was a special assistant in the Los Angeles Angels organization prior to accepting the White Sox job, which he believes is a tremendous opportunity.
"The on-field talent is amazing, and the front office, led by Kenny Williams and Rick Hahn, has done everything necessary to create an atmosphere of long-term success," La Russa said in a statement.
La Russa returns to the White Sox after starting his managerial career in 1979 with the team. He acknowledged that he's changed his previously stated opposition to kneeling during the U.S. anthem.
"Not only do I respect (protests), but applaud the awareness," the four-time Manager of the Year said, according to Paul Sullivan of the Chicago Tribune.
La Russa also said that he doesn't believe celebrations like those that have become a trademark of star shortstop Tim Anderson are a problem.
"If I see that it's sincere and directed towards the game, that's displaying the kind of emotion you want," he added.
The hiring has ruffled the feathers of a number of White Sox employees, reports Jeff Passan of ESPN. They're questioning whether La Russa can connect with younger players and adapt to the game after being away for nine years.
La Russa replaces Rick Renteria, who was fired in mid-October despite Chicago's first playoff appearance since 2008. The club was knocked out of the postseason this year after losing to the Oakland Athletics in the wild-card series.