Ed Reed picked off McNabb's replacement, Kevin Kolb, and returned the interception an NFL-record 108 yards for a touchdown to give Baltimore (7-4) a 22-point cushion with 7:24 left.
McNabb was 8-for-18 for 59 yards with two interceptions and a fumble in the first half - a miserable 13.2 quarterback rating. One week earlier, he threw three interceptions and lost a fumble in an overtime tie with Cincinnati.
Seven turnovers in seven quarters was evidently enough for Philadelphia coach Andy Reid, who turned to Kolb, a second-round pick who didn't throw a pass as a rookie last year and had attempted nine throws this season.
In fairness to McNabb, he didn't get much support from the running game: the Eagles (5-5-1) gained 35 yards rushing in the first half, and McNabb had 7 of them.
It is believed to be the first time that McNabb was benched for ineffectiveness in his 10-year career. He had previously missed time only because of injuries.
Kolb failed to cure the ailing Eagles offense, going 10-for-23 for 73 yards and two interceptions.
Philadelphia's only touchdown came on a 100-yard kickoff return by Quintin Demps in the first half.
Baltimore went up 12-7 in the third quarter when Jameel McClain blocked a punt by Sav Rocca and the ball bounced out of the end zone.
Matt Stover kicked a field goal to launch a 24-point fourth quarter that included a 53-yard touchdown pass from Joe Flacco to Mark Clayton, Reed's interception return and a 1-yard TD run by Le'Ron McClain.
Reed returned two interceptions for a total of 151 yards - more than the passing yardage of both Philadelphia quarterbacks. Reed avoided several tackles on the right sideline during his end zone-to-end zone run.
Following a first quarter that featured five punts, the Ravens forced McNabb into two turnovers and started both drives in Philadelphia territory. But after Jarret Johnson returned a fumble 24 yards to the 48 and Fabian Washington took an interception to the 43, Baltimore punted each time.
The defensive struggle continued until late in the half, when the teams combined for 17 points in 1 minute, 23 seconds.
The surge began when the Eagles went three-and-out before punting from their own end zone. An 18-yard return by Yamon Figurs and a 10-yard penalty for tripping gave Baltimore the ball at the Philadelphia 28, Stover kicked a 44-yard field goal.
On the first play after the kickoff, Reed picked off a McNabb pass and returned it 43 yards to the Philadelphia 6. On third down from the 1, Flacco threw a pass that Daniel Wilcox snagged with his left hand and brought down in the right side of the end zone.
But Demps followed with his kickoff return, the longest by a rookie in Eagles history.