Coach Rick Pitino was visibly upset after watching Louisville come up short in a game it was expected to win over the weekend.
A victory Wednesday night could be all the more difficult to come by without suspended guard Chris Jones.
The 12th-ranked Cardinals will be without their third-leading scorer at Syracuse as these former Big East rivals meet for the first time as members of the ACC.
Nearly two years have passed since Louisville stormed back from 16 down to beat the Orange 78-61 in the Big East championship March 16, 2013. The Cardinals, who have won nine of the last 12 matchups, went on to win the national title in both teams' last season in the conference.
Louisville (20-5, 8-4), which moved to the American Athletic Conference in 2013-14 before joining the ACC, is tied for fourth place in the league after dropping two of three. It fell 52-47 at then-No. 3 Virginia on Feb. 7 and suffered a stunning 74-65 home loss to North Carolina State on Saturday.
Jones had 20 points and Wayne Blackshear added 19, but Terry Rozier and Montrezl Harrell were limited to seven apiece on a combined 4 of 16 from the floor. The Cardinals shot 32.8 percent and only came up with two steals.
"In past years when we shot poorly like this, our defense could carry us through, but it didn't tonight," Pitino said. "I think our guys are not like my other teams.
"They let points dictate. If they're not scoring, they don't play great defense. We've always had the mindset that we're always going to play great defense regardless of whether we score or not."
Points may not be easy to come by without Jones, who was suspended Tuesday for a violation of team rules. The senior is averaging 13.6 points and a team-best 3.7 assists.
Despite Pitino's claim, his team is allowing 59.0 points per game to rank second in the league. The Orange aren't far behind at 63.1, but they've surrendered an average of 76.4 in their last five.
Syracuse (16-9, 7-5) hung tough before falling 80-72 to No. 4 Duke on Saturday. Junior Michael Gbinije scored a career-high 27 points for the Orange, who were outrebounded 42-32 and outscored 19-6 at the foul line.
"I just don't think right now we're good enough to win these games," coach Jim Boeheim said. "I think we've improved, I think we are improving, but we still have to get better. We'll see what happens."
The Orange have dropped all four matchups against Top 25 opponents, though the first three came on the road. Syracuse has taken 13 of its last 18 home games against ranked teams.
"All the games we've had have been tough. We haven't had any games that aren't tough so I think we're prepared," Boeheim said of Wednesday's showdown. "We haven't had an easy game in a long time."
Gbinije is averaging 23.7 points while shooting 67.5 percent over a three-game stretch. Rakeem Christmas leads the team with 17.7 points per game, but he's totaled 18 on 8-of-25 shooting in the last two.
Harrell and Christmas rank third and fifth in the ACC with 9.3 and 9.2 rebounds per game.
The Cardinals are 15-0 when Harrell, averaging 15.4 points, scores at least 13. He had 20 against the Orange in March 2013.