Thaddeus Young scored 20 points and Spencer Hawes had 15 for the Sixers.
Greg Monroe missed a tip with less than a minute left that came back to haunt Detroit. Holiday sank a 19-footer for a 100-95 lead and the Sixers stretched the lead from the free-throw line.
Monroe and Brandon Knight had 22 points apiece. Rodney Stuckey scored 19 for Detroit, and Tayshaun Prince finished with 16.
The Sixers shook off a tough loss at Boston and sluggish first half against Detroit before pulling away in the second half for the win.
Jason Richardson scored 13 points for Philadelphia, including an unusual tiebreaking 3 that made it 83-80 in the fourth. Richardson's shot rattled around the rim, shot up off the top of the backboard and plopped through the net.
Holiday's pull-up jumper made it 98-93 and the Sixers seemed to have some breathing room with 1:53 left.
The Pistons were 0-8 when they came to Philadelphia last month and thumped the Sixers 94-76. They pulled within three in this one before Monroe's miss around the basket helped cost them a second straight upset win.
The 76ers opened the third quarter with a 14-0 run, turning a three-point halftime deficit into a 60-49 lead.
Holiday buried a 3 during the spurt and Hawes picked up his play after a poor first half.
The Pistons recovered and pulled within three after Jason Maxiell's thunderous dunk over Young. In one of the odder box scores to that point, Maxiell missed his first 10 shots to go along with 11 rebounds. He wouldn't score again or grab another rebound.
Taking a temporary break on press row, Sixers CEO Adam Aron fretted that the Pistons were making the game too close. Knight promptly hit a 3 that tied it at 71. Perhaps looking for better luck elsewhere, Aron left for better seats.
Hawes hit an 18-footer to end the third and give the Sixers a 76-75 lead.
NOTES: Former 76ers great Darryl Dawkins was at the game. ... 76ers C Andrew Bynum says pain in his left knee is keeping him from making his debut. His injured right knee is feeling better but even walking causes pain in his left. He'll have his knees examined again Dec. 20th.