The two teams enter the midweek contest off the back of contrasting domestic results on Saturday, with the Citizens forced to settle for a 1-1 draw away at Nottingham Forest in the Premier League, while Die Roten Bullen cruised to a 3-0 victory over Wolfsburg in the Bundesliga.
Ending the campaign with top-flight silverware remains in sight for both clubs, with Leipzig sitting just four points behind Bayern Munich at the Bundesliga summit, while City are two points adrift of Premier League leaders Arsenal, although the Gunners do have a game in hand.
Pep Guardiola and Marco Rose will now put their domestic campaigns to one side as they return to Champions League action, with the former's team regarded as firm favourites to progress to the quarter-finals.
Man City are competing in the Champions League knockout rounds for the 10th successive year after finishing top of Group G above Borussia Dortmund, Sevilla and Copenhagen, while Leipzig bounced back from a shaky start in Group F to finish as runners-up behind Real Madrid.
The two teams will now renew acquaintances over a two-legged tie in the last 16 after previously locking horns in the group stage of last season's competition.
It is fair to say that the first-ever meeting between the two clubs was a cracker, with Man City coming out on top in a nine-goal thriller to kick-start their Group A campaign in emphatic fashion.
Leipzig's Christopher Nkunku - who is available for Wednesday's clash after three months out with an knee injury - experienced a bittersweet night at the Etihad Stadium as he came away on the losing side despite netting a memorable hat-trick in a 6-3 defeat; the Frenchman is one of only two players along with Lionel Messi in October 2016 to score a Champions League hat-trick against City.
Six different names were on the scoresheet for City, meanwhile, including a first-half own goal from Leipzig's Nordi Mukiele either side of strikes from Nathan Ake and Riyad Mahrez, the latter converting from the penalty spot to give the Citizens a 3-1 lead at the interval.
Jack Grealish then scored on his Champions League debut in the second half, before Joao Cancelo and Gabriel Jesus also found the net, while the dismissal of former City man Angelino rubbed salt into Leipzig's wounds in the closing stages.
The fate of both clubs was already decided before they would meet again three months later in their sixth and final Group A fixture, with City confirmed as group winners and Leipzig forced to settle for third spot. However, Die Roten Bullen got their revenge over the Citizens to claim a 2-1 victory in a behind-closed-doors clash at the Red Bull Arena.
Dominik Szoboszlai beat the offside trap before rounding Zack Steffen to put Leipzig in front on the 24-minute mark, and the hosts would have been two goals ahead had Steffen not pulled off a miraculous save from point-blank range to deny Andre Silva with a close-range header.
However, Silva was able to double Leipzig's advantage midway through the second half with a drilled right-footed strike from the centre of the penalty area.
Mahrez then pulled one back for Guardiola's side in the 76th minute with an uncharacteristic diving header at the far post, but hopes of a late comeback were dealt a blow just six minutes later when Kyle Walker was shown a straight red card for stupidly kicking out at Silva.
Prior to that defeat, City had put together a 15-game unbeaten run against German opposition, winning five and drawing one of their last six matches away from home in the process.
Leipzig, meanwhile, had won two of their previous three home meetings with English teams, beating Manchester United 3-2 in December 2020 and Tottenham Hotspur 3-0 in March 2020 - the only exception being a 2-0 loss to Liverpool in February 2021.
RB LEIPZIG VS. MANCHESTER CITY HEAD-TO-HEAD RECORD
Leipzig wins: 1
Man City wins: 1
Draws: 0
Leipzig goals: 5
Man City goals: 7
MATCH HISTORY
September 15, 2021: Manchester City 6-3 RB Leipzig (Champions League group stage)
December 12, 2021: RB Leipzig 2-1 Manchester City (Champions League group stage)
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