After sitting out the Cavaliers' win against the Milwaukee Bucks on Tuesday, James made his way back into the line-up in impressive fashion, posting a game-high 26 points at Cintas Center.
The four-time MVP scored 10 of those points in the third quarter, while he had four rebounds and three assists as Cleveland extended their unbeaten pre-season campaign to four games.
Australian team-mate Matthew Dellavedova and AJ Price contributed 14 points apiece for the Cavaliers.
High-profile recruit Kevin Love sunk five points and four rebounds in 17 minutes.
Chris Copeland was the go-to man for Indiana with 16 points off the bench.
David West (15 points), George Hill (11 points), Rodney Stuckey (10 points) and Luis Scola (10 points) made contributions for the Pacers.
The Brooklyn Nets were 129-117 winners over the Sacramento Kings in overtime.
Brooklyn led 112-109 with 41 seconds remaining before Omri Casspi sunk a three-pointer to send the game into overtime.
But the Kings were outscored 17-5 in the additional period as the Nets improved to 3-0 in pre-season.
Mirza Teletovic starred for Brooklyn, shooting 22 points.
Mason Plumlee added 18 points, while Brook Lopez had 16 points.
Kings pair Ben McLemore (22 points) and Rudy Gay (21 points and seven rebounds) combined for 43 points.
In other results, the Detroit Pistons accounted for the Charlotte Hornets 104-84.
Brazilian side Flamengo were beaten 106-88 by the Orlando Magic.
The Toronto Raptors outscored the Boston Celtics by 12 points in the third quarter to eventually prevail 92-89.
Meanwhile, the Washington Wizards downed Israeli outfit Maccabi Haifa 101-95.