The League One pair will be joined in Southern Group H by League Two's Stevenage and Tottenham Hotspur Under-21s, with the top two progressing to the knockout rounds.
Cambridge are still riding the momentum that saw them promoted from League Two last season and have shown plenty of confidence in their first few games in the third tier.
They come into this match on the back of two consecutive league victories - an impressive 3-0 win against promotion-chasing Burton Albion, followed by a 1-0 win at home to Bolton Wanderers on Saturday.
The U's grinded out the victory thanks to a Shilow Tracey goal after 16 minutes - his first for the club on his fifth appearance - and some well-drilled defending in a cagey affair.
That moves Cambridge up to 10th in the table, which is their highest position in the Football League rankings in over 20 years. Nonetheless, they will be taking on a team above them.
Oxford have come agonisingly close to promotion in the last two seasons, losing to Wycombe Wanderers in the playoff final in 2020 and then falling at the semi-final stage last campaign.
Karl Robinson will be hoping it is third time lucky for his side and they have started the campaign strongly, currently sitting third on 10 points.
After two consecutive losses - including being knocked out of the EFL Cup by Queens Park Rangers - the other U's bounced back with a strong win at home to Lincoln City.
James Henry was the hat-trick hero, with two strikes from distance in the first half and a penalty in the second securing a 3-1 victory.
The two Uniteds met in the opening game of the season, where they played out a 1-1 draw, but it is Oxford who have the better record in this fixture, winning three of the pair's last five meetings.
Cambridge United were dealt a huge blow with club captain Greg Taylor suffering an injury that will see him miss a large portion of the season.
Conor Masterson was brought in on loan immediately from QPR to cover the defensive problem and has performed very well as part of the defensive line in a 4-2-3-1 setup.
Oxford striker Henry returned from a hamstring issue to fire in his hat-trick and will surely continue as part of a three-man midfield, most likely alongside Alex Rodriguez and former Liverpool academy prospect Cameron Brannagan.
Cambridge United possible starting lineup:
Mitov; Williams, Jones, Masterson, Iredale; Digby, O'Neil; Brophy, Hoolahan, Tracey; Ironside
Oxford United possible starting lineup:
Stevens; Forde, Moore, Thorniley, Seddon; Henry, Rodriguez, Brannagan; Sykes, Whyte, Taylor
We say: Cambridge United 0-1 Oxford United
Both sides will want to avoid defeat in the opening fixture of this competition, but we are backing the away side to edge it. They have more experience and should be able to go one better than the draw on the opening day.