The team, led by Bobby Petrino in his fourth year at the school, played their home games in Papa John's Cardinal Stadium.

[5] From the defense, end Elvis Dumervil was taken by Denver, linebacker Brandon Johnson by Arizona and tackle Montavious Stanley by Dallas.

Woodson threw a pair of touchdown passes at the end of the half to bring the teams into halftime with the Cardinals leading 31–14.

Despite the loss of Bush, the Cardinals still managed to score four more touchdowns in the game, including two by his replacement, George Stripling.

The Cardinals next went on the road to face the Temple Owls led by second-year head coach Al Golden and quarterback Adam Dimichele.

The second half wasn't better for the Owls, still failing to score and giving up two more rushing touchdowns and a pair of field goals by Art Carmody.

Prior to the game, Hurricane players came to midfield to stomp on the Cardinals logo, causing a small altercation.

The Cardinals, led by Brohm, scored on a field goal and a long touchdown pass to take a 10–7 lead at halftime.

His loss didn't stop the Cardinals offense though, with running back Kolby Smith scoring two rushing touchdowns in the third quarter, and Brohm's replacement, Hunter Cantwell, throwing another touchdown in the fourth to bring the final score to 31–7 in favor of the Cardinals.

The Wildcats, led by first-year head coach Ron Prince and quarterback duo Josh Freeman and Dylan Meier, were 3–0.

The Cardinals next went on the road to face the Middle Tennessee Blue Raiders, led by first-year head coach Rick Stockstill and quarterback Clint Marks.

The Cardinals scored on an early field goal, but the Blue Raiders took the lead when Damon Nickson returned the ensuing kickoff 88 yards for a touchdown.

Clint Marks threw a touchdown in the fourth quarter, but it was too late for the comeback, giving the Cardinals a 44–17 win.

The Bearcats, led by third-year head coach Mark Dantonio and quarterback Dustin Grutza, though struggling with a 3–3 record on the season, had played number 1 ranked Ohio State and highly ranked Virginia Tech, and had held early leads on both.

After the half, the Cardinals scored on an Anthony Allen rush and another field goal by Art Carmody to have a 23–10 lead in the fourth quarter.

The Orange, led by second-year head coach Greg Robinson and quarterback Perry Patterson, were looking for their first conference win in two years.

The Cardinals next had their biggest game of the season playing the third ranked West Virginia Mountaineers, led by sixth-year head coach Rich Rodriguez and quarterback Pat White.

White led the Mountaineers on a 92-yard drive capped by his second rushing touchdown to bring them with nine at the end of the third quarter.

The Cardinals next went to Rutgers to face the undefeated, 14th ranked Scarlet Knights, led by sixth year head coach Greg Schiano and quarterback Mike Teel.

On the ensuing kickoff, however, Jajuan Spillman returned the ball 100-yards for a touchdown to give the Cardinals a 15–7 lead at the end of the first quarter.

After the Cardinals were unable to score on their first drive in the fourth quarter, the Knights tied the game on a Jeremy Ito field goal.

The Cardinals next faced the Pittsburgh Panthers, led by second-year head coach Dave Wannstedt and quarterback Tyler Palko.

The Panthers tied the game midway through the quarter, but Brohm's second touchdown pass gave the Cardinals a 24–17 lead at halftime.

The Cardinals last regular season game was against the Connecticut Huskies, led by eighth-year head coach Randy Edsall and quarterback Matt Bonislawski.

The Huskies finally scored again, late in the fourth quarter, on a run by Terry Cauley, however it was not enough and the Cardinals won, 48–17.

With the win and Rutgers' loss to West Virginia, the Cardinals won the Big East and the conference's spot in the BCS.

In the third quarter, Skinner tied the game on a 30-yard touchdown pass and took a three-point lead in the fourth after a 36-yard field goal.

Included on the first team were Harry Douglas, Renardo Foster, Kurt Quarterman, George Bussey, Art Carmody, William Gay, and Amobi Okoye, who was a unanimous selection.

[37] After the season, head coach Bobby Petrino and quarterback Brian Brohm were each honored as a finalist and semifinalist for prestigious national awards.

Michael Bush, who had a medical redshirt and was eligible for another year, decided to leave,[42] and was selected in the fourth round by Oakland.