James added nine assists, seven rebounds and delivered a resounding dunk with 2:41 left that effectively put away the Sixers.
The Cavs were down by six points entering the fourth, but held Philadelphia to 4 of 23 shooting from the field in the final quarter to win for the 10th time in 12 games after an 0-2 start.
Lou Williams scored 22 and Thaddeus Young had 21 for the Sixers. Andre Iguodala had 12 but was 6 of 22 from the field - only 1 of 7 in the fourth.
Playing their fourth game in five nights and without center Shaquille O'Neal for the fifth straight game, the Cavs could have been excused for being tired down the stretch.
But they dug down and found some needed energy to hold off the scrappy Sixers, who took an 81-75 lead into the fourth.
James, who scored 40 in a win on Friday at Indiana, was on the bench when the Cavs caught the Sixers at 83-all on a jumper by Williams. The score was tied at 85 when James returned, and the superstar didn't need long to help the Cavs open some breathing room after an uneven performance through three periods.
After Zydrunas Ilgauskas scored on a putback, James fed Jamario Moon for an alley-oop dunk to make it 89-85. Mo Williams then hit Moon on a bounce pass for another dunk, and James, who had his headband knocked off, scored to cap an 18-4 run that made it 93-85. Nothing was clicking for Philadelphia on offense, mostly because the Cavs finally decided to work hard with their backs to the basket. Moon was instrumental in slowing down Iguodala, the Sixers' leading scorer.
Philadelphia ended a nearly five-minute drought with four straight points, but James drove the lane and blasted a two-handed dunk to put the finishing touches on Cleveland's win.
The Cavs' early season has been a streaky one. They are essentially resting O'Neal for the second half and a title push, and the team is still trying to figure out what to do with guard Delonte West, who has been working through personal and legal issues.
"They're going for the gold, man," Sixers coach Eddie Jordan said. "They're doing what they think is necessary to win the championship."
There have been times when the Cavs appear to be going through the motions, and that was the case for much of the first three quarters.
NOTES: Allen Iverson's toughness and scoring touch once symbolized the Sixers. However, the guard remains without a team, a fact James finds unfortunate. "He's a person I watched growing up," James said, "and when you see a person who has talent and still loves the game and wants to be a part of this league, it's kind of strange not having him. It doesn't seem right." Iverson was recently released by Memphis. On Friday, the Knicks announced they would not sign him. ... Sixers G Jason Kapano sat out with a sprained left ankle. He was injured in the fourth quarter Friday. ... Ilgauskas played in his 721nd career game, second most in Cavs history behind general manager Danny Ferry's 723.