The two programs, whose campuses are separated by a little more than an hours drive, will meet for the 53rd time on Thursday night at UC's Nippert Stadium.
For the players, the rivalry with the Bearcats is nearly on par with the game against Kentucky.
"I just think it is a little different," said junior Jake Smith, pointing out that there is often more on the line against the conference foe. "Whenever we play Cincinnati there's always a lot at stake. I know the winner of this game has a chance to win the AAC title and that's the way it is most years. I feel like the stakes are higher."
Senior defensive end Marcus Smith agreed.
"It's always been a great battle with Cincinnati," he said. "It's always a hard fought game. I wouldn't say the rivalry is like a lot of other rivalries around the nation that you see, but when we go out there and play this game, we know that we are going to have to come out and play hard because we know they are going to come out and fight."
A win on Thursday night would also guarantee the Cardinals a spot in the Russell Athletic Bowl held at Orlando's Florida Citrus Bowl Stadium.
"Obviously state pride and bragging rights come into play with Kentucky, but with Cincinnati it seems a little more relevant as far as conference rankings go," said Smith. "UK is our biggest rival, but Cincinnati is right there next to them. The guys that we recruit, the areas we recruit, the conference we play in... the way this rivalry has worked out these last few years and the way some of the games have transpired, I think it really plays a big role."
Nearly two weeks ago, a few Bearcat players turned to social media to 'talk trash' about the upcoming game against the Cardinals.
Louisville's response was to the point. Do the talking on the field.
"We saw it," said senior linebacker and Cincinnati native Preston Brown. "I don't really pay attention to that kind of stuff. We like to do our talking with our shoulder pads."
"We don't do that stuff," added junior safety Calvin Pryor. "Cincinnati is a talking team. That's what they do. We're just getting prepared for what's going to be a great game."
The winner of the game is awarded the Keg of Nails, a trophy signifying that the players are tough as nails. After defeating Cincinnati 34-31 last season, the Cardinals are currently in possession of the Keg and with no future games scheduled due to U of L's move to the ACC, retaining it is important.
"That's big," Pryor said. "Nobody knows when we'll play them again, so we really want to make sure that it comes back here."
The small confines of Nippert Stadium will be filled for the nationally televised contest.
"It is going to be crazy," senior defensive end Marcus Smith said. "I feel like the fans for Cincinnati will pack the house and it will be a hostile environment. As a team, we have been through this before, like playing Rutgers last year. I think we are prepared and we will be ready to go on Thursday."
While there are no future games scheduled, having a continuing series with the Bearcats would be preferred, but may not be frequently possible.
"You have to look at your schedule in the ACC and with the non-conference games," said head coach Charlie Strong. "You would like to continue to play it, but I don't know if you will be able to because you look at who you play in conference. Do you really want to load up seeing as your conference schedule is tough?"
The series, which dates back to 1929, overlaps conference memberships in the Missouri Valley, Metro, Conference USA, Big East and American Athletic Conferences. The Bearcats won the first 12 games of the series and currently hold an overall record of 30-21-1.