SYRACUSE, N.Y. -- Bobby Petrino wore a satisfied look after his latest victory -- another defensive masterpiece for Louisville's offensive guru.

Brandon Radcliff ran for 110 yards and two touchdowns, and Louisville had two interceptions and two safeties in a 28-6 victory over Syracuse on Friday night, the Orange's third straight loss.

"Our defense played really well," Petrino said. "They did a great job. They were fast and physical and did a nice job of communicating and doing what we needed to do."

The Cardinals (5-1, 3-1 Atlantic Coast Conference) moved to 4-0 against Syracuse under Petrino. With a grueling schedule ahead, Syracuse (2-3, 0-1 ACC) began ACC play with a thud, getting just a pair of field goals from Cole Murphy, one in each half.

Louisville entered the game leading the nation in rush defense, allowing only 58.2 yards per game and 1.95 yards per carry, and maintained its stifling play. Syracuse, which was averaging 245 yards rushing a game and 5.7 per carry, gained 27 yards on 13 carries in the first half and fell behind 12-3.

The Orange finished with 59 yards rushing on 25 carries and 255 yards total on offense.

"We thought going in that it was going to be a defensive battle," Syracuse coach Scott Shafer said. "Unfortunately, we didn't do a good enough job. We just came up short."

Entering the game, the series was tied 6-6, the Orange evening the count two years ago in the Carrier Dome when the teams were Big East members. Syracuse rolled to a 45-26 victory over the Teddy Bridgewater-led Cardinals to snap a three-game losing streak in the series. It was No. 11 Louisville's first loss that season after nine wins and served as motivation for the Cardinals coming into Friday night.

Radcliff scored on a 14-yard run late in the third quarter, and his 29-yard catch-and-run set up freshman quarterback Reggie Bonnafon's 4-yard touchdown pass to Gerald Christian midway through the fourth as the Cardinals pulled away.

Quarterback Terrel Hunt, a dual threat and the Orange's leading rusher at 74.8 yards per game the key to the offense, finished with 8 yards on five carries and was 17-of-32 passing for 196 yards before leaving the game late with a leg injury.

"We give all our credit to the d-line," said Louisville linebacker Keith Kelsey, who had a game-high nine tackles. "They made sure they stayed on his low shoulder so he couldn't get out and scramble."

Bonnafon, making his second straight start, was efficient on a night he had to be, completing 12 of 22 passes for 174 yards and shaking off three sacks.

The Cardinals also were ranked third in total defense (225.2 yards per game) and fifth in turnovers gained (13). James Sample nabbed Louisville's 11th interception, tops in the nation, to set up John Wallace's career-best 51-yard field goal late in the first half.

Even when things went right for the Orange, they failed to take full advantage. After Hunt hit wide receiver Ben Lewis for 48 yards to the Louisville 1 on the first possession of the second half, Syracuse had to settle for a 24-yard field goal by Murphy after getting called for penalties on consecutive trick plays.

Tailback Prince-Tyson Gulley's touchdown pass to Lewis was nullified by an ineligible receiver, and wideout Jarrod West's soft throw in the end zone off a reverse was dropped by a wide-open Lewis.

"We needed to rise to the occasion and we had an opportunity," Gulley said. "It's just very hurtful for us not to capitalize on such an easy opportunity."

Trailing 19-6 late in the third quarter, Syracuse got a break when Cameron Lynch stripped the ball from Christian and Wayne Williams recovered for the Orange at the Louisville 44.

No problem for that defense. Gerod Holliman nabbed his nation-leading seventh interception of the season on the next play, stepping in front of Hunt's sideline pass.

Louisville had scored first in every game this season, and after the Cardinals won the toss and Radcliff returned the opening kickoff 64 yards to the Syracuse 36 yard-line, the trend seemed likely to continue. It didn't. The Syracuse defense stuffed Radcliff for a 2-yard loss and sacked Bonnafon for another loss to force a punt.

Julian Whigham's interception halted the Cardinals on their next possession, and the Orange took a 3-0 lead on Murphy's 21-yard field goal midway through the first quarter.

Louisville took the ensuing kick 65 yards on a methodical drive. Bonnafon's 21-yard pass to James Quick and a 10-yard run by L.J. Scott up the gut of the Orange defense gave the Cardinals a first down at the Syracuse 22. Radcliff did the rest with four straight carries, scoring on a 4-yard run for a 7-3 lead late in the first.

Louisville upped the margin to 9-3 early in the second on a safety, thanks in large part to punter Ryan Johnson. After his soaring punt was downed at the 1-yard, Johnson had to re-kick after Louisville was called for a penalty. Again, no problem. His second kick was also downed at the 1, and the Cardinals defense stopped bruising 234-pound Orange tailback Adonis Ameen-Moore in the end zone on second down.

James Sample's interception and 24-yard return to the Syracuse 27 set up Louisville for more late in the second quarter. But the Syracuse defense stiffened, the Cardinals were called for their sixth penalty, and they had to settle for Wallace's field goal.

The Cardinals escaped to the locker room with a 12-3 lead, but just barely. Hunt hit West for 39 yards to the Louisville 2 with 2 seconds left in the second quarter, but Syracuse couldn't get off another play.

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