Griffin fell to the ground clutching his knee and checked out for good after the next Clippers possession.
He played for about a minute longer, but then was taken out by Clippers coach Doc Rivers with 3 minutes, 53 seconds left in the game.
Griffin added 26 points and 11 rebounds.
Without Griffin, the Clippers have little-to-no scoring.
The team have not had the fortune with injuries this regular season.
Griffin left the locker room without speaking to reporters.
The Clippers' next game is Friday (AEDT) against the Jazz in L.A.
The team is already down three starters and could be left with one if the injury is long-term.
Given we can expect the Clippers to play at a pace slightly better than.500 with Griffin, they'd have to be close to even by the time he returns.
Any additional time Griffin misses only adds to the Clippers' hole, and we're counting on them staying healthy after they get Griffin back - not realistic given their injury history. They are now without starters Milos Teodosic (foot) and Danilo Gallinari (hip), while guard Patrick Beverley is lost for the season after knee surgery. And it could well mark the fourth consecutive campaign in which Griffin misses at least 15 games. While there were a few players on the Lakers that performed well offensively, it was hard to find many that played well defensively in this game.
The Clippers are sitting on a 7-11 record without a lot of postseason hopes, so they'll likely err on the extreme side of caution with their franchise cornerstone. Prior to that, he missed most of the 2015-2016 National Basketball Association regular season.