The Magpies have had a strong start to the season and are one of a few teams still unbeaten.
But the Toon have been without a major trophy since the 1960s and Eddie Howe would love to change that.
However, evening trips to struggling League Two teams have proved tricky to Newcastle in the past, so Howe will be keen to avoid any upset.
Micky Mellon's side are three points clear of the drop zone after just one win from their opening five league matches, but they will be well up for this one.
Tranmere v Newcastle: talkSPORT coverage
This Carabao Cup clash will take place on Wednesday, August 24.
Kick-off at Prenton Park is scheduled for 7:45pm.
Coverage starts at 7pm with Adrian Durham.
Commentary will come from Sam Matterface and former England man Trevor Sinclair.
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Tranmere v Newcastle: Team news
The Toon have a few injury concerns with Callum Wilson and Ryan Fraser set to undergo scans to assess hamstring and groin injuries, respectively.
Jonjo Shelvey is their only long-term absentee, while Federico Fernandez and Jamal Lewis have missed every game so far.
But Matt Targett has recovered from a dead leg, so could be involved.
Elliot Anderson has been impressive in training and should start along with Chris Wood.
The likes of Martin Dubravka, Jamaal Lascelles, Emil Krafth, Sean Longstaff and Jacob Murphy could get the chance to impress Howe.
The hosts could rotate with their priority staying in League Two, so the likes of Lee O'Connor, John Nolan and Mateusz Hewlet could come into the side.
Tranmere v Newcastle: What has been said?
Newcastle boss Eddie Howe: "It's very important. I made that clear in pre-season. I want to see a team that wants to win every game we compete in and every competition is treated with the same importance. I hope that's reflected in our performance tomorrow."
Tranmere v Newcastle: Match facts
Tranmere have lost their last five meetings with Newcastle in all competitions, though this is the first time they've faced each other since an FA Cup quarter-final tie in February 2000 (3-2 to Newcastle).
Newcastle won 1-0 in their only previous League Cup meeting with Tranmere, with Kenny Dalglish's son Paul scoring the winner in October 1998.
Tranmere have lost their last six League Cup matches against Premier League sides by an aggregate score of 17-1 since beating Leeds United 3-2 in October 2000.
Newcastle have been knocked out of the League Cup at the second round stage in four of the last five seasons, with the only exception in that run being a 1-0 win over Blackburn Rovers in 2020-21.