8:20 p.m. ET | NBC
Matchup rating: 55.1 | Spread: SF -7 (45)
What to watch for: Can Carson Wentz bounce back against the 49ers’ second-ranked pass defense? Wentz’s early-season struggles have garnered a lot of attention, and coach Doug Pederson said this week he needs to simplify things so Wentz can “unclutter” his mind. The Niners are allowing just 187.3 passing yards per game and would qualify as the best defense Wentz, who has thrown six interceptions and has just a 35.5 QBR, has faced so far this season. — Nick Wagoner
Bold prediction: 49ers tight end George Kittle will score two touchdowns. He has missed the past two games with a knee sprain but returns to a very favorable matchup. The Eagles have allowed four touchdowns to tight ends so far this season, including three by Tyler Higbee in a Week 2 loss to the Rams. Like Sean McVay, Niners coach Kyle Shanahan will exploit the mismatches. If Kittle draws linebacker coverage, look out. — Tim McManus
Stat to know: The Eagles have been outscored by 36 points in the second half this season, the second worst in the NFL ahead of only the Falcons (minus-41). They have outscored opponents by eight points in the first half, though.
What to know for fantasy: Since the beginning of last season, the Eagles are getting a league-high 14.2 fantasy points per week from the tight end position. But Dallas Goedert has an ankle fracture and will be inactive this weekend. See Week 4 rankings.
Betting nugget: San Francisco is 4-17-2 ATS as a home favorite since 2014, including 3-8-2 ATS with Kyle Shahanan as coach (regular season). Read more.
McManus’ pick: 49ers 31, Eagles 20
Wagoner’s pick: 49ers 34, Eagles 17
FPI prediction: SF, 78.8% (by an average of 11.1 points)
Matchup must-reads: Eagles’ Pederson must ‘unclutter’ Wentz’s mind, and his own … After 2017 ‘massacre’ in Philadelphia, 49ers turned their franchise around … Source: Eagles’ Goedert has small ankle fracture … Mullens keeping pylons and the 49ers standing … How an Australian girl with autism forged a bond with the Eagles … Kittle practices; Samuel cleared to return