It marked the sixth straight game Jefferson had at least 20 points and 10 rebounds in a game - extending his own franchise record.
The Bobcats (41-39) remained one game behind the Washington Wizards in the race for the sixth seed in the Eastern Conference with two games left in the regular season. The Wizards defeated Milwaukee 104-91 on Saturday night.
The Bobcats shot 54 percent from the field.
Luke Ridnour, starting in place of injured point guard Kemba Walker, had 12 points and eight assists, in his first start for Charlotte.
Michael Carter-Williams had 23 points and eight assists to lead the 76ers, who have lost 16 of their last 17 games on the road.
The Bobcats were coming off a costly 106-103 loss to Boston on Friday night that dropped them back to seventh in the East standings.
The problem for the Bobcats in that game was their lack of defense - something that plagued them again early on against the 76ers.
Philadelphia took 59-56 at the break despite the Bobcats shooting 62 percent from the field in the first half.
Charlotte would begin to take control late in the third quarter, opening a double-digit lead behind a pair of 3-pointers from Ridnour and Chris Douglas-Roberts, who was one of seven Bobcats to finish in double digits in scoring.
But this game came down to Philadelphia's inability to stop Jefferson in the low post.
Jefferson is averaging 26.1 points and 13 rebounds over the past six games and he showed again why he's an All-NBA team candidate.
Jefferson had his way early on scoring 21 points in the first half on 10-of-13 shooting. He used his old-school style of play to make defenders Henry Sims and Byron Mullens look foolish at times by getting them to leave their feet with pump fakes, leading to easy up-and-under layups.
Philadelphia got 16 points from Thaddeus Young and 15 from Henry Sims, but it wasn't enough for the league's second-worst team.
Still, it was a better showing than last week when the 76ers lost by 30 to the Bobcats on their home floor. They stayed close until the end, when Gerald Henderson helped put the game out of reach with a driving layup.
Henderson finished with 14 points in the win.
NOTES: Bobcats coach Steve Clifford says he hopes Walker will be back for Monday night's game at Atlanta. ... Philadelphia's Jarvis Varnado was a late scratch with a right heel injury. ... The Bobcats have won 24 games at home, the second-most in franchise history.