DeRozan scored 16 points in the fourth quarter, including seven straight early in the period as the Raptors opened a double-digit lead.
Lowry grabbed his 10th rebound late in the fourth, continuing a string of strong games he's had for the Atlantic Division leaders. He's a Philadelphia native and played at Villanova.
The Raptors moved to .500 on the road (11-11) and are 22-20 overall. But the other four teams in the division all have losing records, including Philadelphia, so they've been good enough to sit atop the standings.
Spencer Hawes had 14 points and 12 rebounds for the Sixers. Michael Carter-Williams scored 20.
Lowry was nearly flawless in his latest homecoming, and didn't commit his first turnover until there were about 2 minutes left in the game. He shot 7 of 11 and hit a trio of 3-pointers in 35 minutes to help keep the Raptors in control of the worst division in the NBA.
In a game in which neither team could build much of a lead, DeRozan finally helped the Raptors take control in the fourth. He had a dunk, hit a 3-pointer and nailed a mid-range jumper to give Toronto some breathing room. Patrick Patterson's jumper made it 96-83 for the Raptors.
The Sixers made a short run to close to 98-91 but didn't have enough left for one more rally.
DeRozan scored a career-high 40 points in Toronto's 93-85 win over Dallas on Wednesday night. He connected on 15 of 22 field goal attempts and went 9 for 14 at the free throw line, becoming the seventh player in Raptors history to score 40 points or more.
Against the Sixers, DeRozan made 10 of 22 shots and 13 of 16 free throws.
The Raptors opened the game on a 15-2 run, the Sixers countered with a 20-5 spurt, and from there it was pretty much even.
The Sixers could never get their perimeter game going, scoring 50 of their 78 points through three quarters in the paint. Philadelphia missed 14 of 20 3s overall.
NOTES: The Raptors are 16-8 since they traded Rudy Gay. ... Sixers G Tony Wroten (right ankle) sat out. ... The Sixers signed C Dewayne Dedmon to a second 10-day contract. ... There were 12 lead changes and 15 ties.