The NBA legend announced on Access Hollywood Live that he will appearing in an April 3 episode of the TNT police drama.
O'Neal will be playing Officer Earl Dayton, an old friend of Officer John Cooper (Michael Cudlitz).
The storyline of this episode will see Dayton and Cooper running into each other at the funeral of an alleged gangster.
O'Neal is expected to shoot his scenes for Southland next week in Los Angeles.
His previous acting credits include the films Blue Chip, Kazaam and Steel.
Southland is centred on the dangerous lives of LAPD officers attempting to crack down on crime in the City of Angels.
Gerald McRaney and Chad Michael Murray are also appearing in supporting roles this season.
TNT airs the series on Wednesdays at 10/9c.
Watch Shaquille O'Neal in a trailer for Kazaam below: