SAN FRANCISCO -- Kevin Kolb faked a throw and sprinted away, darting between San Francisco's tacklers as if they were traffic cones before diving forward for a first down on a third-and-18 scramble.
Kolb passed for 253 yards while capably filling in for the injured Vick, and Quintin Mikell returned Alex Smith's fumble 52 yards for a touchdown early in the fourth quarter of the Eagles' 27-24 victory Sunday night.
LeSean McCoy rushed for 92 yards and a score while playing with a broken rib, and Trevard Lindley made a last-minute interception for the Eagles (3-2), who forced five turnovers and survived San Francisco's 14-point surge in the final minutes for their fifth straight win over the 49ers (0-5).
Philadelphia scarcely missed a beat with Kolb making his fourth career start in place of Vick, who hurt his ribs in last week's loss to Washington. The 49ers sacked Kolb four times, but he capably managed the offense during a 21-for-31 performance, hitting tight end Brent Celek for an early score.
"We made it happen when it counted in every aspect of the game," Kolb said. "Our defense was dead tired, and we got those five turnovers and that big one at the end. We had to have this game, and we played with that kind of mentality. Their backs were against the wall, and we played the physical football we needed to win."
Kolb was the Eagles' starting quarterback out of training camp, but sat out with a concussion after the opener while Vick was chosen the NFC's offensive player of the month for September.
"This is part of the maturation process," Philadelphia coach Andy Reid said. "He stepped up and played the way we know he can play."
McCoy made a 29-yard scoring run shortly before halftime for the Eagles, who stayed even with Washington and the New York Giants atop the NFC East by winning their first three road games of a season for the first time since 2004.
Philadelphia's defense yielded 364 yards, but repeatedly made big plays.
"They turned the ball over so much," McCoy said. "They would drive down the field and couldn't finish. We just focused on closing the game out, and we counted on our defense to bail us out at the end."
While Kolb had a fairly smooth night, Smith had perhaps the craziest evening of his six-year career.
The former No. 1 pick passed for 309 yards, but also committed three turnovers that led to thunderous boos from the San Francisco crowd and a tongue-lashing from coach Mike Singletary, who challenged his quarterback to step up as a leader. Smith talked Singletary out of sending in backup David Carr in the fourth quarter before defiantly leading two scoring drives.
"I'm going to keep on going out there until they tell me I'm not," Smith said.
After throwing TD passes to Vernon Davis and Frank Gore, Smith got the 49ers past midfield again in the final minute, but he was hit by Trevor Laws while making a throw. Lindley intercepted the wobbling pass with 28 seconds to play, and the 49ers dropped to their worst start in 31 years with their third loss this season by three points or fewer.
"We knew they were going to come out with a give-it-all-they've-got mentality," Kolb said. "We wanted to match them in intensity from the start."
After David Akers missed a 53-yard field goal on the first snap of the fourth quarter, the 49ers drove past midfield before Smith fumbled while running backward under pressure from Brandon Graham. Mikell picked up the ball and made an untouched run to the end zone for the first defensive touchdown of his eight-year career.
Gore also fumbled twice near midfield.
"You can't win with turnovers, and we seem to have problems with ball security every game," said receiver Michael Crabtree, who had nine catches for 105 yards.
San Francisco, Buffalo and Carolina are the NFL's only winless teams.
When Smith followed his fumble with three incomplete passes on the next series, chants of "We want Carr!" echoed throughout the stadium. After a pep talk from Davis, Smith immediately led a 69-yard scoring drive prominently featuring Davis, who caught a 36-yard pass and a pinpoint 7-yard TD throw with 7:35 to play.
Kolb then led a drive capped by Akers' 45-yard field goal with 4:35 left, but Ted Ginn Jr.'s 61-yard kickoff return set up Smith's swing pass to Gore for a 1-yard TD with 2:02 left.
"I think a pretty decent football team is 0-5," Singletary said. "I'm disappointed for them, because we put ourselves in this situation. Only we can get ourselves out."
Longtime Eagles RB Brian Westbrook received his first handoff of the season with the 49ers, gaining 6 yards in the first quarter. It was his only carry. ... Eagles DT Brodrick Bunkley strained his elbow in the first quarter. ... The Niners lost their first seven games of a 2-14 season under first-year coach Bill Walsh in 1979.
Jets cornerback Antonio Cromartie added fuel to the New York rivalry when he explained why he thinks Giants star wideout Odell Beckham Jr. is a "one-year wonder."
Brian Hoyer is the Houston Texans' starting quarterback for the team's Week 6 game against the Jaguars. For how long he remains beyond that game is uncertain.
The Seattle Seahawks have ruled running back Marshawn Lynch out for Sunday's game against the Cincinnati Bengals due to a hamstring injury.
New Orleans Saints first-round draft pick Andrus Peat will make his starting debut at left tackle against the Eagles in place of injured Terron Armstead.
Stephen Gostkowski of the New England Patriots is the best kicker in the NFL, according to an NFL Nation survey of his peers.
Detroit Lions vice chairman Bill Ford Jr. said Friday on WJR Radio that his mother, owner Martha Ford, is in full control of the franchise.