Die Roten Bullen managed to hold the Premier League champions to a 1-1 draw in the first leg three weeks ago, but tackling the Citizens on their own turf could be a whole different kettle of fish.
Match preview
Perhaps adding a few more pounds to his value, in-demand centre-back Josko Gvardiol saved Leipzig's bacon in the first leg of their last-16 tie against Man City, whose failure to kill the game off forced them to shake hands on a stalemate in Germany.
Riyad Mahrez's strike on the 27-minute mark put the English champions in the ascendancy, but Leipzig came out a different beast after the interval and deservedly levelled through Gvardiol's header with 20 minutes remaining, leaving the tie delicately poised ahead of Tuesday's reunion.
Still fighting for success on three fronts this term, Pep Guardiola's men have embarked on a four-game winning streak since being thwarted at the Red Bull Arena, but only an Erling Braut Haaland penalty could sink a dogged Crystal Palace in a 1-0 Selhurst Park success on Saturday evening.
Seeking to avoid a first last-16 exit since going down to Monaco in the 2016-17 campaign, Man City have a place in the quarter-finals and a slice of history on the line this week, as they could equal Arsenal's 14-year record for the longest Champions League unbeaten home run by an English team.
Indeed, the Citizens have remarkably not lost in 23 home matches in Europe's premier competition - winning 21 of them - and their current winning streak at the Etihad across all tournaments stands at six matches since their New Year's Eve draw with Everton.
In order to inflict Man City's first home defeat of 2023 upon them, Marco Rose must take a leaf out of the book of midweek counterpart Guardiola, who was the last manager to lead a German club to a Champions League win at the Etihad with Bayern Munich in 2013-14.
Since then, nine attempts from Bundesliga powerhouses to get the better of Man City on their own turf have ended in failure, but Leipzig's five-game unbeaten run in the Champions League should stand them in good stead as they seek to inflict more European misery on their sky blue colleagues.
Warming up for this tie in ideal fashion, Rose's side eased to a 3-0 victory over Borussia Monchengladbach in Saturday's Bundesliga contest, where Gvardiol once again demonstrated his proficiency in the opposition penalty area following strikes from Timo Werner and Emil Forsberg.
However, a 2-1 loss to Borussia Dortmund earlier this month ended a nine-game unbeaten run on the road in all competitions for Leipzig, whose manager Rose has incredibly faced Man City in all three Champions League knockout games that he has taken charge of so far - the 46-year-old's Monchengladbach side succumbed to City's superiority in the 2020-21 season.
The Etihad faithful were treated to a glut of goals when Man City put a Christopher Nkunku-inspired Leipzig to the sword 6-3 at the Etihad in 2021, and all three meetings between two sides seeking an elusive European honour have seen both teams find the back of the net.
Manchester City Champions League form:
W
W
D
D
W
D
Manchester City form (all competitions):
D
D
W
W
W
W
RB Leipzig Champions League form:
L
W
W
W
W
D
RB Leipzig form (all competitions):
L
W
D
W
L
W
Team News
With Phil Foden managing to recover from a scare over a foot injury to line up at Selhurst Park, Guardiola is set to be working with a fully-fit squad for the second leg, meaning that 'Pep roulette' could very well come into play.
After being named on the bench for the win over Crystal Palace, Kevin De Bruyne certainly ought to force his way back into the first XI, while Riyad Mahrez and Kyle Walker - despite recent allegations of flashing against the latter - can also expect recalls.
Mahrez was afforded a complete rest at the weekend, and the Algerian's penchant for goals against Leipzig should no doubt work in his favour when it comes to Guardiola's selection - he has scored in all three of his Champions League fixtures against Die Roten Bullen so far.
As for Leipzig, Etihad hat-trick hero Nkunku has picked up a fresh hamstring problem since recovering from a long-term knee injury and is expected to miss out, joining Xaver Schlager, Peter Gulacsi and Abdou Diallo on the sidelines.
Nkunku and Schlager both sustained their issues in the loss to Dortmund on March 4, and the latter could miss the rest of the season due to an ankle ligament tear, and Rose's squad was also decimated by infection prior to the win over Gladbach.
Werner, Konrad Laimer, Dominik Szoboszlai and Lukas Klostermann were all reported to have been feeling under the weather, but all four of them made the squad on Saturday - the latter was only an unused substitute, though.
Manchester City possible starting lineup:
Ederson; Walker, Akanji, Dias, Ake; De Bruyne, Rodri, Gundogan; Mahrez, Haaland, Grealish
RB Leipzig possible starting lineup:
Blaswich; Henrichs, Orban, Gvardiol, Halstenberg; Laimer, Haidara; Szoboszlai, Forsberg, Werner; Silva
We say: Manchester City 2-1 RB Leipzig (Man City win 3-2 on aggregate)
Defences do not normally come out on top when Man City and Leipzig lock horns, and we can see a similar theme continuing here, even with the absent Nkunku unable to replicate his terrific treble from 18 months ago.
However, home advantage and injuries to integral Leipzig players will no doubt work in the Citizens' favour, and while patience may be the name of the game - as it was at Selhurst Park - Guardiola's men should prevail by a narrow margin to keep their Champions League fantasy alive.