Evan Turner scored 12 points for the Sixers, who moved a half-game ahead of Boston and back into sole possession of first place in the Atlantic Division. The Sixers have held the top spot in the Atlantic for all but a few days early in the season.
The Sixers romped without forward Andre Iguodala, who missed his second straight game because of left patella tendinitis. Meeks started in his place and made the most of his opportunity, making 7 of 10 3-pointers.
Anthony Parker scored 14 points and Kyrie Irving had 12 for the Cavaliers, who dropped their fourth straight.
The Sixers were one of the early season surprises in the NBA when they rolled to a 20-9 start. But a tougher schedule, various injuries to center Spencer Hawes, and trying to win big without a superstar caught up with the Sixers and they hit a rough patch.
The Sixers have gone 8-14 since that start but never lost their grip on first - or fourth place in the East. Had the Sixers lost to Cleveland, they would have tumbled to seventh in the conference standings.
Even without Iguodala, their top perimeter defender, the outcome was never in doubt Tuesday.
The Cavs scored the game's first five points before Meeks got hot from 3-point range and led the Sixers on a 12-0 run. He scored 12 points in the first quarter, Holiday took over in the second (4 of 6, eight points), and the Sixers led 57-43 at halftime.
Meeks started the first 38 games of the season before coach Doug Collins benched him with the Sixers in a 2-8 funk. Meeks had started 102 straight games when Collins decided to give Turner, the 2010 No. 2 overall draft pick, a turn in the backcourt. Meeks was scuffling from 3-point range at the time of his benching, but he had that long-range stroke going against the Cavs.
Meeks' sixth 3-pointer topped his previous career best of 26 points and stretched the lead to 96-78. With Meeks leading the way, the Sixers made 10 of 19 3-pointers.
The Cavaliers had another uninspired effort in another season headed toward the draft lottery. After the Cavs were flat in a loss to Phoenix on Sunday, coach Byron Scott ran them harder in practice on Monday than he had since training camp.
It didn't matter, not with the way Meeks was torching them from outside.
Notes: Cavaliers G Daniel Gibson has a torn tendon in his left foot and ankle and will likely miss the remainder of the season. ... The Sixers are 13-2 when they score 100 points. ... The Sixers have the opposition below 100 points in 19 of the last 20 games.