The two outfits prepare for battle in Group B of the Northern Section, where Port Vale and Crewe Alexandra are also vying for the two spots into the second round.
Match preview
After enjoying life as the big fish in the small National League pond last season, Wrexham have slowly but steadily adjusted to life back in the English Football League, only suffering one defeat from their first six contests in the fourth tier.
Phil Parkinson's men were hit for five on the opening weekend against MK Dons but have since gleaned a respectable nine points from their last 15 on offer, picking up a trio of draws to complement a duo of wins against Walsall and most recently Tranmere Rovers.
Replacing the goals of Paul Mullin would ostensibly be an arduous task, but the Red Dragons remain as prolific as ever in the final third, and centre-back Aaron Hayden came up with the telling contribution against Tranmere, heading home the game's only goal with 56 minutes on the clock.
Before their stint in the doldrums of non-league, Wrexham were crowned EFL Trophy champions in the 2004-05 season thanks to a 2-0 extra-time win over Southend United in the final, where Darren Ferguson was on target at the Millennium Stadium.
However, the Red Dragons suffered three first-round exits in their subsequent EFL Trophy campaigns and have already been subjected to one dose of knockout heartache this season, losing on penalties to Bradford City in the second round of the EFL Cup after previously getting the better of Wigan Athletic from 12 yards.
Meanwhile, Newcastle's Under-21 team can empathise with the seniors when it comes to dismal starts to the campaign, as while Eddie Howe's side lost their third Premier League game in a row to Brighton & Hove Albion at the weekend, the youth team were subjected to their third successive beating at home to Manchester City in the Premier League 2.
Following a 4-1 drubbing at Tottenham Hotspur and 1-0 loss on Reading's territory, Newcastle returned to familiar surroundings Whitley Park for the visit of the champions, but Ben Dawson's side were taught another footballing lesson in a 4-0 humbling.
With just one win to show from their opening four matches of the campaign, the Magpies sit 22nd in the 26-team development league, while they have also been unable to make waves during their recent EFL Trophy campaigns either.
Indeed, Newcastle Under-21s have failed to progress beyond the group stage in five of their six appearances in the competition - including each of their last four - and their only run to the knockout stages in 2018-19 ended with a 4-0 loss to arch-rivals Sunderland in the last 16.
That painful defeat to the Black Cats marked the first of 13 straight EFL Trophy defeats for Newcastle Under-21s - who do have the disadvantage of playing all their ties away from home - but such an appalling record will no doubt have Wrexham licking their lips at the prospect of a midweek mauling.
Wrexham form (all competitions):
D
W
D
D
L
W
Newcastle United Under-21s form (all competitions):
W
W
W
L
L
L
Advert - content below:
Team News
As mentioned, Wrexham have been forced to navigate their summer fixtures without the talismanic Mullin due to the 28-year-old's collision with then-Manchester United goalkeeper Nathan Bishop, which left the striker with broken ribs and a punctured lung to boot.
However, Parkinson recently revealed that Mullin is now being put through his paces on the training pitches as he steps up his recovery, but it will still be some time before the attacker is considered for a competitive return.
The hosts will also be without veteran winger James McClean following his call-up to the Republic of Ireland squad, so Jacob Mendy should occupy the left flank in Parkinson's recognisable 3-5-2 shape, while Arsenal loanee Arthur Okonkwo might be considered for his debut in goal.
While Wrexham are only without one international representative, Newcastle have lost four players to call-ups, including Lewis Miley, who has been selected to don the England colours at Under-19 level.
Defender Cathal Heffernan will turn out for the Republic of Ireland's Under-18s, while compatriots Reece Byrne and Alex Murphy are one level above with the Under-19s, although the latter came off injured just before the break against Man City.
Charlie McArthur will likely deputise for Murphy in a left-back role, while Lewis Miley's older brother Jamie Miley should hold the fort in the engine room in his sibling's absence.
Wrexham possible starting lineup:
Okonkwo; Hayden, Boyle, Tozer; Barnett, O'Connor, Young, Lee, Mendy; Palmer, Dalby
Newcastle United Under-21s possible starting lineup:
Smith; Thompson, Savage, Wiggett, McArthur; J. Miley, Carlyon, Huntley; Parkinson, Stephenson, Diallo
We say: Wrexham 3-0 Newcastle United Under-21s
Even with Mullin helplessly watching on from the medical room, goals have not been too hard to come by for this Wrexham crop, who should start as they mean to go on in the EFL Trophy.