Wentz was 18 of 32 for 211 yards and now has tossed a franchise-record 19 touchdown passes through the first eight games.
The Eagles improved to 7-1 following their sixth consecutive win while the 49ers fell to 0-8, joining the Cleveland Browns as the only two teams without a win.
San Francisco quarterback C.J. Beathard was under heavy pressure much of the game and finished 17 of 36 for 167 yards, one touchdown and two interceptions.
The Eagles went ahead 20-0 when rookie kicker Jake Elliott nailed a 51-yard field goal with 8:01 left in the third quarter.
It was Elliott's fifth field goal this season of at least 50 yards, a new franchise record.
The 49ers didn't wilt as Ahkello Witherspoon intercepted a pass, setting up what would be a 21-yard shovel pass for a touchdown from Beathard to running back Matt Breida. The score cut the lead to 20-7 with 4:29 remaining in the third.
Philadelphia wasted little time in responding as Alshon Jeffery hauled in a 53-yard touchdown pass from Wentz for a 27-7 advantage.
LeGarrette Blount later plunged in from 12 yards for a 33-7 lead though Elliott missed the extra point, his second of the game.
The Eagles couldn't do much offensively for a while, but struck for a pair of touchdowns 27 seconds apart for a 17-0 advantage just before halftime.
Wentz connected on a 1-yard touchdown pass to tight end Zach Ertz, which was set up by a pass interference penalty on 49ers cornerback Dontae Johnson, with 1:51 remaining.
On San Francisco's next possession, Beathard was intercepted by cornerback Jalen Mills, who weaved in and out of defenders and across the field for a 37-yard touchdown. Wentz converted the two-point conversion with a pass to Jeffery.
NOTES: Eagles CB Ronald Darby (ankle) made a late push to play this week, but was declared inactive. ... The 49ers were without key players such as LB Reuben Foster (rib, ankle) and RT Trent Brown (concussion). ... Lane Johnson started at right tackle while Halapoulivaati Vaitai got the start at left tackle for the Eagles in place of the injured Jason Peters. ... San Francisco head coach Kyle Shanahan is still in search of his first victory. ... The Eagles haven't allowed a touchdown in the first quarter in 10 consecutive regular-season games. ... 49ers FS Jimmie Ward left the game in the first quarter with a forearm injury and didn't return. LT Joe Staley left with an eye injury.