The Panthers began their season with a Week 1 duel with the Philadelphia Eagles. They were playing with Jake Delhomme, who had five interceptions, and one fumble in their postseason game, last year, vs. the Arizona Cardinals. In the first quarter, Carolina pounced first with running back DeAngelo Williams getting an 11-yard touchdown run. The Eagles would respond with kicker David Akers getting a 49-yard field goal. In the second quarter, Philadelphia took control as Panthers quarterback Jake Delhomme lost a fumble, which was recovered by defensive end Victor Abiamiri and returned two yards for a touchdown. Also, wide receiver DeSean Jackson returned a punt 85 yards for a touchdown, and quarterback Donovan McNabb completed a 9-yard touchdown pass to tight end Brent Celek and a 4-yard touchdown pass to running back Brian Westbrook. The Panthers would close out the period with kicker John Kasay nailing a 22-yard field goal. Afterwards, in the third quarter, the Eagles closed out their domination as McNabb got a 3-yard touchdown run.
With the loss, Carolina began its season at 0–1.
Delhomme (7-of-17 for 73 yards) was benched after committing five turnovers (four interceptions and a fumble).
Hoping to rebound from their loss to the Eagles, the Panthers flew to the Georgia Dome for a Week 2 NFC South duel with the Atlanta Falcons. In the first quarter, Carolina delivered the first scratch as kicker John Kasay got a 38-yard field goal. The Falcons would answer with quarerback Matt Ryan completing a 24-yard touchdown pass to tight end Tony Gonzalez. The Panthers would retake the lead in the second quarter as running back DeAngelo Williams getting a 3-yard touchdown run, but Atlanta would reply with Ryan completing a 10-yard touchdown pass to running back Jason Snelling. Carolina would gain some ground as Kasay nailed a 50-yard field goal, but the Falcons would close out the half with Ryan completing a 7-yard touchdown pass to wide receiver Roddy White. After a scoreless third quarter, Atlanta would pull away as running back Michael Turner getting a 1-yard touchdown. The Panthers would try to rally, but get only get an 11-yard touchdown pass from quarterback Jake Delhomme to tight end Dante Rosario.
Still looking for their first win of the season, the Panthers flew to Cowboys Stadium for a Week 3 Monday night duel with the Dallas Cowboys. After a scoreless first quarter, Carolina would get the lead in the second quarter with quarterback Jake Delhomme's 25-yard touchdown pass to tight end Dante Rosario. The Cowboys would take the lead in the third quarter with kicker Nick Folk's 24-yard field goal and running back Tashard Choice's 5-yard touchdown run. Dallas would get a further grasp on the lead in the fourth quarter with Folk's 19-yard field goal and cornerback Terence Newman returning Delhomme's 7th interception of the season 27 yards for a touchdown (with Choice getting the 2-point conversion run). The Panthers tried to rally, but the Cowboys' defense would prevent their comeback from happening.
With the loss, Carolina entered its bye week at 0–3.
Following their bye week, the Panthers returned to Charlotte to face the Washington Redskins. After a DeAngelo Williams fumble, the Redskins struck first blood with quarterback Jason Campbell's 10-yard touchdown pass to running back Clinton Portis. During the second quarter, linebacker Thomas Davis and defensive end Julius Peppers tackled Portis in the endzone for a safety, making the score 7–2. The Redskins responded with a 39-yard field goal by kicker Shaun Suisham. During the third quarter, cornerback DeAngelo Hall intercepted quarterback Jake Delhomme's pass and took it to the one, with Clinton Portis capping it off with a touchdown run, making it 17–2. The Panthers then scored on a 17-yard touchdown catch by tight end Jeff King. In the fourth quarter, kicker John Kasay booted a 43-yard field goal, decreasing the lead to 17–12. After a botched punt return by the Redskins, Carolina scored on an 8-yard run by running back Jonathan Stewart. With the two point conversion pass to wide receiver Steve Smith, Carolina took a 20–17 lead. After a Washington punt, the Panthers ran out the clock with an 8-yard run by Jake Delhomme.
With the comeback win, the Panthers improved to 1–3.
Coming off their win over the Redskins, the Panthers flew to Raymond James Stadium for a Week 6 NFC South duel with the Tampa Bay Buccaneers. Carolina would trail in the first quarter as Buccaneers running back Carnell Williams got a 20-yard touchdown run, yet the Panthers would tie the game in the second quarter with a 20-yard touchdown from running back DeAngelo Williams.
In the third quarter, Carolina took the lead with quarterback Jake Delhomme's 1-yard touchdown pass to tight end Jeff King and running back Jonathan Stewart's 26-yard touchdown run. Tampa Bay would immediately answer with wide receiver Sammie Stroughter returning a kickoff 97 yards for a touchdown. The Buccaneers would tie the game in the fourth quarter as safety Tanard Jackson returned an interception 26 yards for a touchdown, but the Panthers got the last laugh as Williams got a 1-yard touchdown run.
With the win, Carolina improved to 2–3.
Cornerback Dante Wesley was ejected from the game in the second quarter after ramming into Buccaneers kick returner Clifton Smith. He would later get a one-game suspension.
Coming off their divisional road win over the Buccaneers, the Panthers went home for a Week 7 interconference duel with the Buffalo Bills. Carolina would find themselves trailing in the first quarter as Bills running back Marshawn Lynch got a 7-yard touchdown run. The Panthers would respond in the second quarter as defensive tackle Hollis Thomas tackled running back Fred Jackson in his endzone for a safety.
After a scoreless third quarter, Buffalo got a big play in the fourth quarter as quarterback Ryan Fitzpatrick completing a 2-yard touchdown pass to wide receiver Lee Evans, followed by kicker Rian Lindell nailing a 29-yard field goal. Carolina tried to recover as running back DeAngelo Williams got a 15-yard touchdown run, but the Bills would seal the win with Lindell's 22-yard field goal.
In the first quarter, Carolina would begin the game with a 6-yard touchdown run from running back Jonathan Stewart. The Cardinals would answer with quarterback Kurt Warner completing a 14-yard touchdown pass to running back LaRod Stephens-Howling. The Panthers would take a commanding lead in the second quarter as Stewart got a 10-yard touchdown run, quarterback Jake Delhomme hooked up with wide receiver Steve Smith on a 50-yard touchdown pass, and defensive end Julius Peppers returned an interception 13 yards for a touchdown.
In the third quarter, Arizona began to rally as Warner connected with tight end Ben Patrick on a 1-yard touchdown pass. Carolina would answer in the fourth quarter with a 35-yard field goal from kicker John Kasay. The Cardinals tried to pull off a comeback as running back Tim Hightower got a 1-yard touchdown run, yet the Panthers closed out the game with Kasay's 31-yard field goal.
With the amazing win, Carolina improved to 3–4.
The Panthers' defense had a field day on Warner, recording 5 interceptions and a fumble recovery.
Coming off a defensively-strong performance against the Cardinals, the Panthers flew to the Louisiana Superdome for a Week 9 NFC South duel with the undefeated New Orleans Saints. Carolina got off to a fast start in the first quarter as running back DeAngelo Williams got a 66-yard and a 7-yard touchdown run. The Saints would get on the board in the second quarter as kicker John Carney made a 23-yard field goal. The Panthers came right back as kicker John Kasay nailed a 32-yard field goal, but New Orleans would close out the half as Carney booted a 25-yard field goal.
In the third quarter, the Saints continued to hack away as running back Pierre Thomas got a 10-yard touchdown run. Carolina answered with Kasay's 25-yard field goal, but New Orleans would tie the game to end the period as quarterback Drew Brees completed a 54-yard touchdown pass to wide receiver Robert Meachem. Afterwards, the Saints would pull away in the fourth quarter with Carney's 40-yard field goal, followed by defensive tackle Anthony Hargrove forcing a fumble from Williams and returning it 1 yard for a touchdown.
Hoping to rebound from their tough divisional road loss to the Saints, the Panthers went home for a Week 10 NFC South rematch with the Atlanta Falcons. Carolina would trail early in the first quarter as Falcons kicker Jason Elam booted a 35-yard field goal, yet the Panthers came right as running back Jonathan Stewart got a 1-yard touchdown run. Carolina would add to their lead in the second with quarterback Jake Delhomme hooking up with wide receiver Steve Smith on a 4-yard touchdown pass, yet Atlanta would answer with a 1-yard touchdown run from running back Jason Snelling. The Panthers would close out the half with Delhomme's 4-yard touchdown pass to Smith.
In the second half, the Falcons began to erase their deficit as Elam nailed a 24-yard field goal in the third quarter, followed by quarterback Matt Ryan completing a 3-yard touchdown pass to tight end Justin Peelle. Afterwards, Carolina would pull away as Stewart got a 45-yard touchdown run.
Coming off their divisional home win to the Falcons, the Panthers went home for a Week 11 Interconference duel with the Miami Dolphins. In the first quarter, Carolina got on the board first with John Kasay hitting a 29-yard field goal. In the second quarter the Dolphins replied and took the lead with Chad Henne getting a 14-yard touchdown pass to Ricky Williams, and a 1-yard touchdown run from Williams again. After a scoreless third quarter the Panthers slightly improved as John Kasay nailed a 33-yard field goal, until Miami kept it a 2-possession game when Dan Carpenter got a 37-yard field goal. The Panthers would keep hopes alive as Jake Delhomme made a 27-yard touchdown pass to Steve Smith (with a successful 2-point conversion made by DeAngelo Williams). The Dolphins would pull away as Ricky Williams made a 46-yard touchdown run. The 48-yard field goal made by John Kasay near the end of the game wasn't enough for the Panthers and that resulted in a loss.
With both teams coming off of tough losses, the Panthers went on the road to face the formidable defense of the New York Jets in what was on paper a close matchup. Both teams sported identical 4–6 records and were top 3 in rushing offense, while sporting similar numbers in pass defense game. Things started out well for Carolina, their first drive taking almost 6 minutes of clock to drive down into Jets territory when bad luck struck them. A miscommunication between Jake Delhomme and Steve Smith resulted in a pass being fired at Smith while he wasn't looking, and it caromed off of Smith's leg into the arms of Jets' CB Darrelle Revis, who returned it 67 yards for a TD. It was the first of Delhomme's 4 INTs of the day, two each by Revis and safety Kerry Rhodes. Rhodes' first set the Jets up in good field position, which the Jets were able to capitalize on when Thomas Jones ran the ball in for a 4 yard TD. The Panthers soon after that struggled to do anything against the Jets defense and secured only two John Kasay field goals for a 17–6 defeat.
The Panthers fell to 4–7 and wound up losing Jake Delhomme to a broken finger on his throwing hand.