Vick, who suffered a rib injury during the loss to the Washington Redskins this past Sunday, will not travel with the team to San Francisco.
That means Kevin Kolb will be the starting quarterback for the Eagles. Kolb said he felt confident after a week of preparation.
"We had an unbelievable week of work. Our intensity level's been through the roof, and I feel like we have a great game plan, so those three things need to combine into a victory," Kolb said.
CB Asante Samuel and WR Riley Cooper, who both suffered concussions, are also out for Sunday.
Meanwhile, RB LeSean McCoy, who suffered a broken rib, is listed as questionable. The Eagles said, however, that McCoy should be able to play. He did participate in practice on Friday.
Head coach Andy Reid said Monday that Vick suffered a rib cartilage injury in Sunday's loss to the Washington Redskins, but sustained no broken bones.
Vick was forced out in his first start in front of the hometown crowd.
It was late in the first quarter when Vick took two hard hits, getting sandwiched between Kareem Moore and DeAngelo Hall after a dazzling 23-yard run to the Redskins 1 that was negated by a holding penalty.
He was replaced by Kevin Kolb, who suffered a concussion in the season opener that allowed Vick to take the starting quarterback job.
Kolb struggled in his first meaningful action of the season, going 22 for 35 for 201 yards with a touchdown and interception.