The Citizens will be seeking revenge at the Red Bull Arena after losing their previous visit 2-1 in the group stage of last season's competition.
Match preview
Qualifying from the Champions League group stage seemed a tall order for Leipzig earlier this season after losing their first two matches against Shakhtar Donetsk and Real Madrid, but the German outfit bounced back to win their remaining four games - including an impressive 3-2 home victory over Los Blancos - and qualify as runners-up of Group F.
Those four wins took place during an impressive 18-game unbeaten run across all competitions between October 1 and February 11, which was eventually brought to an end courtesy of a 2-1 home loss against Union Berlin in the Bundesliga.
Marco Rose's side returned to winning ways last weekend, though, as they breezed to a 3-0 away victory over Wolfsburg to keep them in the mix for the Bundesliga title. Leipzig currently sit fifth in the table but there are just five points separating the top six teams with 13 games remaining.
Leipzig are sure to have one eye on upcoming clashes with sixth-placed Eintracht Frankfurt and second-placed Borussia Dortmund, but they must first turn their attention back to the Champions League and prepare for their third last-16 encounter with an English club, having previously beaten Tottenham Hotspur 4-0 on aggregate in 2019-20 before losing to Liverpool by the same scoreline in 2020-21.
Die Roten Bullen - who lost to Rangers in the Europa League semi-finals last season - will reminisce about the aforementioned home triumph over Man City last season, which saw Dominik Szoboszlai and Andre Silva both on the scoresheet before Kyle Walker was sent off in the closing stages.
Leipzig will be aware of the challenge that awaits them on Wednesday, but they can enter the contest with confidence of claiming a positive result against a City side who are hoping to rediscover their mojo following an inconsistent spell of form.
Just three days after securing a 3-1 away victory over Premier League title rivals Arsenal, Man City were dealt a blow in the quest to retain their top-flight crown as they were held to a 1-1 draw away at Nottingham Forest on Saturday.
A dominant Citizens side, who boasted 73% possession and 23 shots across the 90 minutes, were in front at the break courtesy of a 41st-minute strike from Bernardo Silva, but they were made to rue a plethora of missed chances before Chris Wood tapped home an 84th-minute equaliser for Forest.
Pep Guardiola's side have now failed to win four of their last five away matches in all competitions, while they have dropped seven points in as many Premier League games, leaving them two points adrift of leaders Arsenal having played a game more than the Gunners.
A return to the Champions League is next on the agenda for City, and the pressure is on Guardiola to lead the club to glory for the first time in their history having previously admitted in December that his time as City manager will not be "complete" if he fails to win Europe's elite club competition.
The Citizens are competing in the Champions League knockout rounds for the 10th successive year after winning four and drawing two of their six group-stage matches earlier this season to top Group G ahead of Borussia Dortmund, Sevilla and Copenhagen. They now enter Wednesday's clash with Leipzig seeking to advance from the last 16 for the sixth consecutive season.
Prior to the group-stage loss against Leipzig last season, City had put together a 16-game unbeaten run against German opposition in the Champions League, including a thrilling 6-3 victory over Leipzig at the Etihad Stadium in September 2021. The Citizens will hope for another emphatic showing in front of goal on Wednesday as they bid to gain an advantage to take into next month's second leg on home soil.
RB Leipzig Champions League form:
L
L
W
W
W
W
RB Leipzig form (all competitions):
W
W
W
D
L
W
Manchester City Champions League form:
W
W
W
D
D
W
Manchester City form (all competitions):
W
W
L
W
W
D
Team News
Leipzig will be without Peter Gulacsi (ACL), Dani Olmo (thigh) and Abdou Diallo (knee) due to injury, but the Germans have been handed a boost regarding the fitness of Christopher Nkunku and Konrad Laimer, who both came off the bench last weekend.
Nkunku made his long-awaited return after three months on the sidelines with a knee injury, but it remains to be seen whether he is fully fit to start on Wednesday, so Andre Silva could continue up front with support provided in the final third by Timo Werner, Emil Forsberg and Dominik Szoboszlai.
Laimer managed to shake off a thigh issue to feature against Wolfsburg and he could return to the first XI to partner Xaver Schlager in centre-midfield, while highly-rated centre-back Josko Gvardiol is set to continue alongside Willi Orban, who returned to the side against Wolfsburg after a week away to donate stem cells.
Rose may consider making changes at full-back, with Lukas Klostermann hoping to fend off competition from Mohamed Simakan and Benjamin Henrichs for the right-back role, while Marcel Halstenberg will be pushing to start ahead of David Raum at left-back.
As for Man City, John Stones remains out as he continues to recover from a hamstring injury, but otherwise Guardiola has a fully fit squad at his disposal.
Guardiola has made at least one change to his defence in each of the last 11 matches in all competitions, and further alterations could be on the cards against Leipzig, with Nathan Ake, Manuel Akanji and Rico Lewis all hoping to force their way back into the first XI.
Bernardo Silva is expected to continue in his makeshift left-back role, drifting into a deep-lying midfield position alongside Rodri when City are in possession, while Kevin De Bruyne and Ilkay Gundogan will likely keep their places in the middle of the pitch.
Riyad Mahrez could be recalled to the starting lineup at the expense of either Phil Foden or Jack Grealish, while Erling Braut Haaland - who has scored six goals in four previous meetings against Leipzig - is set to lead the line ahead of Julian Alvarez.
RB Leipzig possible starting lineup:
Blaswich; Klostermann, Orban, Gvardiol, Raum; Schlager, Laimer; Szoboszlai, Forsberg, Werner; Silva
Manchester City possible starting lineup:
Ederson; Walker, Akanji, Ake; Rodri, Bernardo; Mahrez, De Bruyne, Gundogan, Grealish; Haaland
We say: RB Leipzig 1-2 Manchester City
Excluding the away triumph over Arsenal, Man City have been far from their best on the road in recent weeks, and another challenging encounter could be in store on Wednesday as Leipzig have previously shown their threat going forward against the Citizens.