The Swans are current holders of the competition and beat Valencia 3-0 in the Europa League last week.
Clark, whose side hammered Sheffield Wednesday 4-1 on Saturday, knows it will be a testing night for his men.
"In my opinion, it's the hardest tie outside of the (Premier League's) top six for various reasons," he said.
"Swansea's a club on the up, not just the team as it's been a club on the rise for many years.
"They are the holders of the competition and they're sweeping everybody aside at this moment in time in no matter what competition they play.
"I was at West Brom and Swansea won that game comfortably. They went to Valencia, not an easy place, and won that game comfortably and then they did the same at Crystal Palace over the weekend.
"They will make changes, but I think their squad is that strong and the philosophy of how they want to play never changes that we know it's going to be a tough game."
As Leeds prepare to head to Newcastle in the third round of the Capital One Cup on Wednesday night, one of their biggest problems this season has been a lack of goals.
The Whites have scored just seven in the Sky Bet Championship and are still searching for an adequate replacement for Luciano Becchio who was sold to Norwich in January.
Saturday's 2-1 home defeat to Burnley was their third loss in the last four games, but although they have been linked with David Bentley, manager Brian McDermott has distanced himself from a possible loan move for the former Arsenal and Tottenham midfielder, who has been a free agent since his release from White Hart Lane at the end of last season.
"We've got Ross McCormack in there and we've got El-Hadji Diouf in there, and they are similar players," McDermott told the Leeds' official website..
"I think David Bentley is a good player, but they're here and in that mould and the last thing you want to do is stockpile players in the same position. That isn't right."
Leeds will monitor Sam Byram, who made his first appearance of the season at the weekend following a long-term hip injury and Lee Peltier (groin), who missed the defeat to Burnley.
But a third full-back, Stephen Warnock, will be available after suspension.
Tranmere may need to take a leaf out of the old Stoke's book if they are to cause a Capital One Cup upset, according to Rovers manager Ronnie Moore.
The Potters are now under the guidance of Mark Hughes and will travel to Prenton Park equipped with a completely different style of football to what fans became accustomed to with former boss Tony Pulis.
While Pulis enjoyed plenty of success in his seven years at the helm, Stoke supporters were critical of his physical brand of long-ball football which was derided by others outside of the Britannia Stadium.
Moore has seen a noticeable change in Stoke this season but believes the type of attributes which became hallmarks of the Pulis era could be adopted by his own team.
"We're too nice and we need to be aggressive," said Moore, whose team have won just once in Sky Bet League One and have conceded 19 times in eight games this season.
"It's hard when you're not really an aggressive person. I'm not saying go out there and boot somebody and kick them in the air, I'm saying be aggressive by closing people down and getting in people's faces.
"These days they come through academies all nicey-nicey, you're really looking for a dog, somebody who is going to sit there in defensive midfield and do a job."