The two teams take up four places in Southern section Group E, where the Gunners beat Leyton Orient 2-1 in their opening tie, while their hosts lost by the same scoreline to Colchester United.
Match preview
Never before has a Premier League academy team gone all the way to EFL Trophy glory, but Arsenal's quest for silverware began in ideal fashion on September 3, where Mehmet Ali's men made a true statement of intent by sinking League One Leyton Orient.
Strikes from Josh Robinson and Ismeal Kabia either side of a response from Dan Happe ensured that Arsenal would be sitting pretty in first place after one matchday, as the young Gunners endeavour to progress to the second round for the fifth tournament running.
That triumph early last month was the fourth of five successive wins for Arsenal's Under-21s, but with former stars Ethan Nwaneri and Myles Lewis-Skelly now fully-fledged members of the first team, Ali's men have been a shadow of their old selves in the past fortnight.
Indeed, an otherwise unblemished September ended with a 3-0 home defeat to Liverpool in the Premier League 2, before Tottenham Hotspur rocked up to Arsenal's territory on Saturday and left with an emphatic 5-2 win under their belts, despite the Gunners being 2-0 ahead at the break.
It made a change for Spurs to be on the right end of a 5-2 scoreline against the Gunners - Arsenal's seniors memorably won back-to-back home North London derbies by that exact margin in 2011-12 and 2012-13 - and such a calamitous collapse could set a couple of alarm bells off.
One-time winners of the EFL Trophy back in the 2007-08 campaign - when it was known as the Johnstone's Paint Trophy - MK Dons are already propping up the Southern section Group E rankings on account of a narrow defeat to Colchester three weeks ago.
Stephen Wearne drew first blood for the League Two side in the 34th minute, but MK Dons were only ahead for all of seven minutes, as Anthony Scully equalised from the spot before Fiacre Kelleher completed the Colchester turnaround nine minutes into the second half.
That 2-1 loss proved to be Mike Williamson's last game as head coach - the 40-year-old jumped ship for MK Dons' fourth-tier rivals Carlisle United a couple of days later - and after 900-appearance defender Dean Lewington took charge for one game, Scott Lindsey is now overseeing operations.
The 52-year-old is yet to suffer defeat since taking the reins, as MK Dons made it four games unbeaten in all competitions with a 1-1 draw against Tranmere Rovers on Saturday, prior to which they ran out 5-1 victors at Harrogate Town.
However, that triumph represents the hosts' only win from their last six matches in all competitions, although a four-game unbeaten home run stands them in good stead before a maiden meeting with Arsenal's proteges.
MK Dons EFL Trophy form:
L
MK Dons form (all competitions):
L
L
D
D
W
D
Arsenal Under-21s EFL Trophy form:
W
Arsenal Under-21s form (all competitions):
W
W
W
W
L
L
Team News
Arsenal goalkeeper Tommy Setford is seemingly still sidelined with an unexplained injury - an issue that allowed 16-year-old Jack Porter to start for the seniors in the EFL Cup against Bolton Wanderers - but the latter is away on international duty this month.
A straight shootout will therefore occur between Lucas Nygaard and Brian Okonkwo for the gloves, and Ali will also have 21-year-old striker Khayon Edwards back from a three-game ban.
Edwards, Kabia and Romari Forde - who scored at the weekend - could form the attacking trident here, but it remains to be seen if captain Nathan Butler-Oyedeji is involved after making the bench for the first team against Southampton.
As for MK Dons, on-loan Southampton defender Nico Lawrence is facing a few more weeks out after a knee operation, while Jonathan Leko has missed most of 2024 after rupturing ligaments in the same area.
Striker Matt Dennis is also sidelined, but MK Dons have just added to their attacking ranks with the signing of 32-year-old Ireland international striker Scott Hogan on a free transfer.
The former Aston Villa and Birmingham City striker will be eligible to make his Dons debut this week, potentially displacing Tommy Leigh at the tip of the hosts' attack.
MK Dons possible starting lineup:
Harness; Lewington, Tucker, Offord; Tripp, Kelly, Carroll, Tomlinson; White, Gibley; Hogan
Arsenal Under-21s possible starting lineup:
Okonkwo; Nichols, Kacurri, Monlouis, Heaven; Gower, Rosiak, Oulad M'Hand; Kabia, Edwards, Forde
We say: MK Dons 2-1 Arsenal Under-21s
Arsenal's last two defensive displays have been highly concerning, and an MK Dons side still enjoying a new manager bounce should be able to exploit such frailties.