Rashard Lewis scored 14 and Norris Cole added 13 for the Heat, whose magic number for clinching the league's best regular-season record was trimmed to two.
Miami moved to 60-16, one win shy of matching the franchise single-season record. The Heat got there after outscoring Philadelphia 29-11 in the fourth quarter.
Jrue Holiday scored 18 points for Philadelphia, which got 14 from Evan Turner and an 11-point, 11-rebound night from Spencer Hawes.
James had missed Miami's last three games, was cleared to return after some pregame testing on Saturday and shot 12 for 17 from the field. The Heat were without Dwyane Wade (sore ankle and knee) and Chris Bosh (sore right knee).
A steal and dunk from James with 2:41 left just about sealed the outcome, giving the Heat - who led by just one entering the final quarter - what was then their biggest lead, a 16-point margin at 101-85.
Miami has now beaten Philadelphia in 19 of the teams' last 20 meetings, including playoffs. In the regular season only, it's 15 straight wins for the Heat.
And while Miami will go into the Eastern Conference playoffs as the No. 1 seed, a disappointing season for the 76ers is winding down without a single appearance from Andrew Bynum.
"We swung for the fences," Philadelphia coach Doug Collins said. "And I give our organization a lot of credit. We went for a home run and unfortunately it didn't work for us this year. But I will tell you, the guys in the locker room, I'm incredibly proud at how hard they've played every single night. We've competed and we've had some really tough losses but we can only grow from that."
Heat coach Erik Spoelstra said before the game that he would carefully manage James' minutes, and he wasn't kidding.
James checked out for the first time after playing 7:45 of the opening quarter, his shortest stint to open a regular-season game since October 2010 - his first week of action with the Heat.
Then again, it didn't seem like the Heat would exactly need much from James at that point.
Miami made its first four 3-point attempts, shot 64 percent in the opening quarter compared with 29 by Philadelphia, and led 33-18 - outscoring the 76ers 20-5 over the final 6:44.
Things flip-flopped in the second quarter.
It was Philadelphia that started dominating from the field (55 percent to Miami's 30), and a 15-8 rebounding edge that quarter helped the 76ers pull within 50-46 at the break. For Miami, it was a statistically odd half, with the Heat shooting far better from outside the 3-point arc - 8 for 13 - than its 13-of-32 pace from 2-point range in the opening 24 minutes.
Holiday scored 11 in the third quarter, including a 3 for 3 effort from 3-point range, and the 76ers were within 77-76 entering the fourth. But the Heat started the final quarter strong. James found Ray Allen for a 3-pointer with 6 minutes left that pushed Miami's lead back to 10, and win No. 60 was in the books a short time later.