SANTA CLARA, Calif. -- After a successful 10-day trip to New Jersey and West Virginia, the San Francisco 49ers returned home Sunday night and looked like a team that left its juice on the East Coast.

The Niners struggled from the start in a disappointing 25-20 loss to the Philadelphia Eagles. The defeat dropped the Niners to 2-2 on the season and 0-2 at Levi's Stadium.

Perhaps of more concern is that this is the latest and, perhaps, costliest in a series of sluggish performances for the Niners after they have had an extended stay back East.

Last season, the 49ers returned from a trip that included wins in Tampa Bay and in Cincinnati with a weeklong stay in Youngstown, Ohio, to eke out a victory against the Pittsburgh Steelers in which they turned it over five times and won on a last-second touchdown. Later in the season, the Niners stayed in Bradenton, Florida, between games against the Baltimore Ravens and New Orleans Saints only to come home and lose to the Atlanta Falcons.

As it turned out, that loss to the Falcons didn't hurt the 49ers, who still went on to clinch the No. 1 seed and surge to Super Bowl LIV. It will take a significant turn of events for Sunday night's loss not to haunt the Niners on a deeper level, though.

Yes, the Niners are missing many key players and, yes, they will get the majority of them back. But with the schedule set to intensify, this was a loss the 49ers simply couldn't afford if they're going to make another push for the postseason and the NFC West Division crown.

QB breakdown: For as sharp as quarterback Nick Mullens was in his first start of the season last week against the New York Giants, he was equally off Sunday night. When Mullens wasn't targeting tight end George Kittle, he was all over the place. Mullens was shaky early on, missing fullback Kyle Juszczyk for a would-be big play and throwing a costly interception in the red zone. He later coughed up a fumble and threw an even worse pick that was returned for a touchdown and resulted in his benching.

Mullens finished 18-of-26 for 200 yards with one touchdown and two interceptions for a passer rating of 72.6. Full-time starter Jimmy Garoppolo is still working his way back from a high right ankle sprain, but he could return as soon as next week against the Miami Dolphins. Based on what happened in this Week 4 loss, his return would be a welcome development for the Niners.

Troubling trend: The 49ers' offensive line again struggled to open holes in the running game and protect consistently, something that has happened more than once in the first quarter of the season. The Niners managed to finish with 116 yards rushing on 20 carries, but it took some gadget plays -- including rookie Brandon Aiyuk's 38-yard touchdown run -- to make that number look better. Of more concern were the five sacks and 15 quarterback hits the 49ers allowed. This group must improve in a hurry if the offense is going to take off when the likes of Garoppolo and running back Raheem Mostert return from injury.