For Leipzig, it's been a disappointing campaign and having recently sacked manager Jesse Marsch, the best they can now hope for is third place and a spot in the Europa League's round-of-32.
When, where and how to watch
When: Tuesday, December 7, 17.45 GMT
Where: Red Bull Arena, Leipzig
How to watch: BT Sport
Best bets for RB Leipzig vs Manchester City
Heading into the chaotic Christmas period, they have hit form at just the right time with seven wins in a row, during which they have scored 18 goals.
That makes difficult reading for Leipzig who are on a three-match domestic losing streak and have kept just one clean sheet from seven outings.
With that in mind, plus the fact that City won the previous meeting in Manchester 6-3, it's not difficult to see them putting a reeling Leipzig to the sword with a winning margin of three or more goals at 19/4.
However, despite Leipzig's recent domestic woes, they did thrash Club Brugge 5-0 in their last Champions League game, so the ability to score is clearly there.
Given that Die Roten Bullen are hurting, the chance of them starting quickly and scoring the game's first goal at 13/10 feels quite high, even if they do ultimately go down to another defeat.
Both teams to score doesn't appeal at 40/85, but considering there are goals in City, a far more tempting 25/1 is available for a correct score prediction of a 4-1 away victory.
Last time out
The sides have only met competitively once before, but there was enough drama packed into that 90 minutes to more than make up for a lack of any previous action.
City prevailed 6-3 in a madcap game at the Etihad Stadium in September, as even Christopher Nkunku's hat-trick wasn't enough to save the visitors.
Nathan Ake netted City's opener and Nordi Mukiele's own goal doubled the lead before Nkunku replied to halve the deficit. Riyad Mahrez then converted a VAR-awarded penalty to make it 3-1 at half-time.
Nkunku again threw Leipzig a lifeline, only for Jack Grealish to score an absolute beauty to restore City's two-goal cushion.
Nkunku completed his hat-trick in a final attempt to salvage something, but late strikes from Joao Cancelo and Gabriel Jesus, either side of a red card for former City man Angelino, finalised the rout.
American Marsch took over at Leipzig from Bayern Munich-bound Julian Nagelsmann in the summer, but was dismissed on Sunday after a 2-1 loss at Union Berlin.
Die Roten Bullen currently sit 11th in the Bundesliga, seven points off the top four, having won just five out of 14 games this term, and are currently on a three-match losing streak.
For Guardiola's City it's an entirely different situation as they are in the midst of a seven-match winning run, and over the weekend, leapfrogged Liverpool to take top spot in the Premier League.
Their most recent game brought a 3-1 win at Watford, in which Raheem Sterling netted the opener before Bernardo Silva's brace made the game safe.
Goalscorer bets for RB Leipzig vs Manchester City
Portuguese midfielder Silva has blossomed in the absence of Kevin De Bruyne - who played for the first time in five games against Watford - and has scored four goals in his last five games.
With De Bruyne now seemingly back at full fitness following his introduction off the bench at Vicarage Road, many would expect the Belgium international to start. On the other hand, how do you drop Silva in his current form.
The 27-year-old knows where the goal is better than anyone in the City squad right now, and can be backed to score again anytime at 14/5.
Nkunku's previous exploits against City should catapult him into the conversation when it comes to goalscorers. In keeping with what we've already said about how this match might go, we're backing him to score first at 6/1.
Indeed, Frenchman Nkunku did in fact find net for Leipzig in that defeat to Union Berlin, so not only does he have previous goals against City, but he also has current form too.
Alternatively, someone else who was impressive against Union was young Hungarian Dominik Szoboszlai, bagging the assist for Nkunku's strike, and he has a wicked right foot that could quite easily strike too at 14/5.