Kolb passed for 253 yards while capably filling in for injured Michael Vick, and Quintin Mikell returned Smith's fumble 51 yards for a touchdown early in the fourth quarter of the Eagles' 27-24 victory over the winless 49ers on Sunday night.
LeSean McCoy rushed for 92 yards and a score, 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).
"We just tried to stick with our game plan and do what we do," Eagles receiver DeSean Jackson said. "Kolb came in and did a great job in place of Vick. That finish scared me a little bit, but I'm glad the troops stayed together."
Smith passed for 309 yards, but also committed three turnovers that led to thunderous boos from the Candlestick Park crowd and an apparent tongue-lashing from coach Mike Singletary. Smith shook it off and defiantly led two fourth-quarter scoring drives.
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."
Kolb made his fourth career start in place of Vick, who injured his ribs in last week's loss to Washington. 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.
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. Kolb also showed off some surprisingly fleet feet with a 19-yard run on a third-and-18 play in the third quarter, dodging between tacklers and ball-faking with a slickness that recalled Vick at his elusive best.
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.
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.
When Smith came out to run the 49ers' offense on the next possession, the crowd hit him with perhaps the loudest boos of his tumultuous six seasons in San Francisco. After three incomplete passes, the chants of "We want Carr!" - for backup David Carr - echoed throughout the stadium.
Smith and Singletary then were seen in an animated exchange on the sideline, but Smith went back on the field with the San Francisco offense.
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, trimming the Eagles' lead to seven points.
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.
Philadelphia immediately made a three-and-out drive featuring a curious incompletion on third down, giving the ball back to Smith with 1:28 left.
