James now has 28,599 points in 1,055 regular-season games, spanning 14 seasons.
James entered Thursday 23 points shy of tying O'Neal and matched the former center with a layup with 7:29 remaining in the game. He moved past O'Neal when he hit a free throw after getting fouled on a 3-point attempt by Rajon Rondo with 4:28 remaining.
The milestone meant little to James after the game as the Cavaliers lost for the fifth time in seven games.
"That means absolutely nothing right now," James said. "I've been healthy enough and I've had some great teammates that allowed me to get to that point. Shaq is an all-time great and the most dominant player to ever play this game. Extremely excited to see him get a statue outside of Staples Center. But I could (not) care less about me passing him. Means absolutely nothing."