The sides have been drawn in Group D alongside Bolton Wanderers and Port Vale, with the top two advancing to the next stage.
Liverpool are one of 16 Premier League academy sides featuring in the tournament and will be aiming to improve on their disappointing showing from last season.
The Reds lost all three games and conceded 13 goals in the process as they exited the competition in the first round.
Indeed, since joining the competition at the start of 2019-20, Liverpool have still yet to win a single match.
The EFL Trophy is supposed to provide Jurgen Klopp's rising stars a chance to impress, but all it has done so far is show there is a big gulf between age-grade and senior football.
Rochdale will therefore feel confident of putting all three points on the board in midweek, but they also exited the competition in the first round last time out.
The Dale were relegated to the fourth tier of English football last season and have made a rather underwhelming start to the 2021-22 campaign.
However, after collecting just one point from their opening three matches, Robbie Stockdale's charges have since defeated Northampton Town and drawn with Colchester United.
It remains to be seen just how seriously Stockdale will take this competition, with next weekend's trip to Port Vale likely taking priority over the two fixtures.
Rochdale are expected to rotate their side between league matches, which could see some fringe players given a chance to impress.
Jay Lynch is not expected to be in contention after sustaining a knock in the warm-up ahead of the Colchester match.
Matteo Ritaccio recently signed a new deal at Anfield and will be looking to take the next step in his career with some promising displays in the EFL Trophy.
Rochdale possible starting lineup:
Coleman; Taylor, O'Connell, Dorsett; O'Keeffe, Dooley, Morley, Keohane; Cashman, Beesley, Odoh
Liverpool Under-21s possible starting lineup:
Hughes; Wilson, Clayton, Boyes, Gallacher; Bearne, Corness, Ritaccio, Longstaff; O'Rourke, Stewart
We say: Rochdale 2-0 Liverpool Under-21s
Liverpool have really struggled in this competition over the past couple of seasons and are still seeking their first EFL Trophy win at the seventh attempt.
Rochdale's priorities may lie elsewhere, but we can see them kicking off their Group D campaign with all three points on Tuesday.
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